myc function and regulation.

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myc FUNCTION AND REGULATION Kenneth B. Marcui,2,3, Steven A. Bosson�, and Amanda J. Patef Departments of Biochemistry and Cell Biology I, Pathology2, and Microbiology3, State University of New York at Stony Brook, Stony Brook, New York 11794 KEY W O RD S:

nuclear oncogenes and malignancy, cell growth and differentiation, gene regulation, leucine zipper proteins, helix-loop-helix proteins

CONTENTS PERSPECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . myc BELO NG S TO A SMALL FAM ILY OF H IGHLY RELAT ED PROTO -O NCOGENES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . General Structure-Function Properties of c-myc Polypeptides . . . . . . . . . . . . . . . . . . . . . . . . . . Light at the End of the myc Tunnel: A DNA-Binding Site and an Elusive Protein Partner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .............. ........

810 811

813 815

EFFECT S O N A ND BY myc IN CELL -CYCL E PROG RESSIO N A ND PROL IFERA TIO N. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .

817

EFFECT S O N A ND BY myc IN D IFFERENT IATO N. . . . . ... . .. ..... ...... . . . . ............ . .

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TUMO RIG ENESIS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .. . . . .

824

A ROL E FO R c-myc IN D NA REPL ICAT IO N: FA CT OR FA NTA SY ? . . . . . . ...........

827

REG ULAT IO N O F myc A ND BY myc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . myc Autoregulation............................................................................... Regulation of Other Cellular Genes by myc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Regulation of myc Transcriptional Initiation................................................ Regulation of myc Transcriptional Elongation.............................................. Other Oncoproteins Contribute co myc Transcriptional Regulation . . . . . . . . . . . . . . . . . . . . Significance of c-myc Antisense Transcription.............................................. Posttranscriptional Control of c-myc Expression...........................................

828 828 830 831 838 841 842 843

MODES O F myc ACT IVATIO N IN MALIG NA NC IES. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Gene Amplification ............................................................................... Proviral Insertion................................................................................. Chromosomal Translocations...................................................................

845 845 846

myc INT ERACT IO NS W ITH T UMO R SUPPRESSO RS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

849

RETRO SPECT IV E. . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . .... . . ..... . . . . .. . . . . . . . . . . .. . .. . . ... . . . . . . .... . . . .

850

845

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0066-4154/92/0701-0809$02.00

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PERSPECTIVES For an oncogene, myc has a rather pivotal spot in the history of the molecular genetics of neoplastic disease. It was only about 10 years ago that myc represented the first example of insertional mutagenesis in malignancy with avian leukosis virus (ALV)-induced B cell lymphomagenesis in chickens (1). This seminal discovery, along with the prior identification of the chicken myc gene as the captured cellular coding sequence of the acutely transforming avian myelocytomatosis virus (AMV), led to a variety of similar findings on a number of cellular genes with oncogenetic potential (2-4). Soon thereafter, the mammalian homologues of the avian myc gene made their way to the scene. An unexpected series of events in a number of laboratories placed the mammalian c-myc locus at the breakpoints of nonrandom chromosome trans locations with immunoglobulin loci, in Burkitt lymphomas in humans and plasmacytomas in mice (5-9). Eight to nine years ago, myc seemed like a neatly wrapped package to all its investigators. The corroborative evidence was overwhelming that myc was an oncogene that played a critical if not essential role in the genesis of avian and mammalian B lymphoid malignan cies by chromosomal rearrangement mechanisms. However, that was only the beginning of the myc saga. A host of research groups have descended upon c-myc in the past 10 years, exploring its complex regulation in a variety of cellular contexts, and the biochemical activities and cellular fates of its polypeptide (7-12). These efforts have generated an impressive amount of data, but most importantly, a number of paradigms for the study of cellular genes that regulate themselves and/or other genes. Studies of c-myc have touched the fields of normal and abnormal cell growth and differentiation, in vitro in culture and in vivo in animals. The controversial biochemical properties of the myc polypeptide have yielded proposals for its potential roles in the transcriptional and posttranscriptional control of other cellular genes and in DNA replication. The greatest leap in the quest to decipher the "myc enigma" arose unexpectedly from the discovery of two classes of transcription factors operationally defined by virtue of one of two common domains of limited structural similarity: the leucine zipper (LZ) (13) and the helix-loop-helix (H-L-H) motif (14). Proteins containing LZ and H-L-H domains have been shown in numerous cases to be sequence-specific DNA-binding factors that regulate the transcription of genes by RNA polymerase II (15). The LZ consists of a 20-30-residue amphipathic a-helix, with a leucine positioned at every seventh residue creating a hydrophobic interface on one side of the helix (13). Zipper proteins also possess a helical stretch of basic amino acids, called the basic region (BR), spaced six residues amino-terminal to their LZ domains. The spatial arrangement of the (BR)LZ domain is related to those of the (BR)H-L-H domains of other transcription


MYC FUNCTION AND REGULATION

811

factors (15). The H-L-H domain consists of two amphipathic a-helices of about 15 amino acids, separated by a spacer segment of varying length which is preceded by a basic region of about 13 amino acids rich in arginines (14). The amphipathic LZ and H-L-H domains are indirectly required for the stable juxtapositioning of two basic regions that facilitate the formation of a homo or heterodimeric protein complex with a specific DNA sequence (13- 15). The c-myc polypeptides contain (BR)H-L-H and LZ domains, and strong evidence is accumulating that they mediate their functions as site-specific DNA binding proteins. The myc polypeptide has significant effects on the growth and differentiation of a variety of diverse cell types, and if expressed in appropriately, the normal protein also contributes to neoplasia. Cells keep myc under very tight regulation. Here, we havc made a valiant effort to review the literature on biological effects mediated directly or indirectly by myc, and on the regulation of the gene, its mRNAs, and its polypeptides. The field is vast and at times controversial. We have pointed out where evidence for various phenomena is weak or strong and the direction(s) in which future efforts are likely headed.

myc

BELONGS TO A SMALL FAMILY OF HIGHLY RELATED PROTO-ONCOGENES In 1983 and 1985 reports appeared on the identification of two amplified coding sequences with strong homology to c-myc in human neuroblastomas and small cell lung carcinomas, which were dubbed the N-myc and L-myc genes respectively (12, 16-18). Each of the three mammalian myc family gencs has the same characteristic three-exon structure with the major polypeptide open reading frame residing in the second and third exons. The first exon of the myc genes is not conserved, but possesses regulatory func tions, which have been definitively established for the murine and human c-myc genes (see below). Highly homologous blocks of amino acids separated by areas of diminished conservation are spread throughout the two coding exons, suggesting early on that myc polypeptides may have discreet, in dependent functional domains (Figure 1). Other cellular sequences have been identified with comparable homology to some portions of c-myc, but available information suggests that they represent pseudogenes ( 19), truncated genes (20, 2 1), and in one instance, a developmentally regulated secondary c-myc allele (22). B-myc contains homology to c-myc exon 2, and encodes a 188-amino-acid protein (20). The B-myc polypeptide could be analogous to the putative protein encoded by shortened human L-myc transcripts that contain only first- and second-exon sequences. B-myc is expressed almost ubiquitously, but its functions remain unknown. A fourth gene, S-myc, exhibits homology to the second and third

8 12

MARCU ET AL

50AA

-

Exon 2

GSRIII p

CI- 109 bp - 1 42 to +513 bpc -40& to - 294 bp +24 to + 140 bp

O(P l ) + (P2) + (P2) + (P2)

blast,) , HeLa

HeLa extracts

c::: Z ("} ...., ..... 0 Z ;l> Z t; :;:0 m 0 c::: l' ;l> ....,

(5

Z

00 � VI


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MARCU ET AL

from P I (CCGCCC) , which is perfectly conserved between human and mouse. Another region of particular interest is - 293 to - 10 1 , which was originally found essential for P I usage and necessary for efficient P2 initiation in gene transfer assays (253 , 256) . More recently , a GGGTGGG sequence motif ( - 142 to - 1 1 5) within this region was found to bind a nuclear factor, PUP (256), as well as a ribonucleoprotein complex (257), and was also deemed necessary for P2 activity in an in vitro transcription assay (256). PuP may reside in the ribonucleoprotein complex, or these may represent distinct factors recognizing the same or overlapping sequences. A factor termed nuclease sensitive element protein-1 (NSEP- 1 ) , which binds to this region, has recently been cloned (R. Kolluri, T. A. Torrey, A. J. Kinniburgh, personal communication). More recently, Postel et al reported that an anti sense oligonucleotide of the PuF-binding site dramatically inhibited P I activ ity in vivo but only had a modest effect on P2 activity. However, the disparity between the in vitro and in vivo data was not addressed (258) . The lack of in vivo footprinting data and trans-activation assays with cloned genes encoding these binding activities make it difficult to assess their relative significance at present. The region between - 142 and - 1 15 contains a purine-pyrimidine rich sequence that can adopt a triple-helical H-DNA conformation, containing S l nuclease and DH sites (256, 259-6 1). A similar region in the chicken and mouse c-myc genes binds multiple proteins including SP I (262, 263). Com mon Factor 1 (CF 1 ) , a ubiquitous transcription factor, binds at - 262 to - 252 relative to P I start, and plasmacytoma-specific factor PRF binds just 5' of CPl at - 290 (264-266) . The PRF site appears to function in a cell-type specific negative manner, but its role in differential PI and P2 usage remains to be determined, while a multimerized CFl site was found to activate transcription of a basal promoter in both B cells and fibroblasts (266) . An NFKB-like factor has been identified in WEHI 23 1 extracts that binds to a sequence - 1 10 1 to - 108 1 upstream of the murine PI start site , and like the CF1 site has the potential to contribute to positive control, since two or more copies activated a heterologous promoter (267). An earlier study focused on a further upstream region of the murine myc gene, between - 1 1 88 and -428, which behaved in the manner of a transcriptional "dehancer" of the myc promoter or other heterologous promotors (268). This negative region was subdivided into two negative elements that bind multiple nuclear factors. However, the dehancer effect was more pronounced with heterologous pro moters in B lymphoid cell lines, making its importance for regulating P 1 - and P2-initiated transcripts less general and possibly cell-type-specific. These negative elements may function by interfering with transcription factors binding near the P I and P2 start sites (269) . Avigan et al have identified an element far upstream of human PI ( - 1 554 to - 1526) termed FUSE. They demonstrate that when HL60 and U937 leukemia cells are induced to dif-


MYC

FUNCTION AND REGULATION

837

ferentiate with DMSO, there is a dramatic decrease in binding to FUSE. The loss of binding correlates closely with a loss of transcription initiation of the endogenous c-myc gene and also with commitment to differentiation (270). Cis-acting elements residing in the c-myc first exon and intron have been proposed to regulate P2 transcriptional initiation. Two control elements (ME l a l and ME l a2) positioned between P I and P2 were first described by Asselin et al (263). MEl a l ( + 96 to + 1 1 9) and MEl aZ ( + 57 to + 8Z) were defined as major target sites for the binding of nuclear factors and are well conserved between the mouse and human genes . Two gel mobility shift complexes were observed with an ME l a l synthetic oligonucleotide; one of these was also observed with the MEl a2 site (S . Bossone and C. Asselin, unpublished results; A. Nepveu, personal communication). Deletion of the MEl aI -binding site resulted in a dramatic reduction of PZ activity in fibroblastic cells and a modest upregulation of P I , but this could be an indirect consequence of reduced P2 function if these nearby start sites normal ly interfere with each other (Z63). Recent findings have shown that an MEl a l site-directed mutant lost virtually all P2 activity with a modest increase i n P I , and the same mutant only generated one instead of two gel shift complexes (S . Bossone, C . Asselin, A. Patel , K . Marcu, submitted for publication) . An MEl aZ site-directed mutant reduced P2 activity , raising the PI :P2 ratio from O . Z to 1 .0 (C . Asselin, unpublished results) . Recently , a human gene encoding a novel zinc finger protein that binds the ME l a l sequence was identified (S . Bossone, C. Asselin, A. Patel, K. Marcu , submitted for publication). Preliminary evidence suggests that this factor is involved in P2 regulation because it failed to bind the mutated MEl a l site described above that inactivated the PZ promoter (S . Bossone, C . Asselin, A . Patel, K . Marcu, submitted for publication) . Hall demonstrated that the MEl a l site was re quired for transcriptional initiation from PZ in an in vitro transcription system (Z7 l ) . A sequence element (GGCGGGAAAA) located between ME l a l and MEl aZ and conserved between mouse and human was differentially required for P2 initiation in different cellular backgrounds (255, 272) and found to bind to the E2F transcription factor (272, 273). Interestingly, this region has also been shown to bind as an RNA to a p55 protein found in HeLa and MEL cells (Z73a). An earlier study identified another positive element downstream of the P2 start site within exon 1 , which behaved like a position-dependent positive modulator of P2 activity (274). This positive element functioned when it was placed downstream of PZ or other heterologous promoters . Removal of 60 bp of DNA at the exon l Iintron 1 junction of the mouse gene diminished PZ activity (Z65 , 274); this region was shown to contain a sequence that resembles the binding site of a nuclear factor in the promoter of a mouse ribosomal protein gene (275). A 37-kDa protein, MBP- l , which binds upstream of human P2, has recently been cloned (276). DNase I �

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protection analysis showed that MBP- l protects a region from + 1 23 to + 1 5 3 relative t o P I just 5 ' o f the P 2 TATA motif, and appears to be a negative regulator of

c-myc transcription from cotransfection experiments with myc

CAT constructs . A 20-bp sequence located at the beginning of intron 1 of the human

myc gene binds a 1 38-kDa nuclear phosphoprotein denoted MIF (277).

The MIF-binding site is inactivated by mutation(s) and rearrangements in Burkitt lymphoma cells, suggesting that it might play a role in limiting

myc

activity (278).


myc transcription initiation can either be upregulated or downregulated in response to growth factors and other stimuli. Growth factors such as TGF-a (85), PDGF (81 , 66, 7 1 ) , IL-2 (279, 280), PHA (280), and ionomycin (280) all can potentially upregulate

myc transcriptional initiation. Furthermore, a

PDGF response element has been identified in the murine c-myc gene, + 36 to + 1 17 relative to P I , which stimulates transcription initiation from PI 3-5fold in the presence of PDGF (28 1 ) . Elevation of

myc initiation was also

shown to occur in B cells treated with anti-Ig antibody (282). TNF-a and TGF-(3 both suppressed c-myc, with TGF-(3 directly affecting initiation (283), but the mechanism of TNF-a inhibition of myc transcription remains to be elucidated (284, 285) . TGF-f3 appeared to interact with an element near PI (+ 100 to - 7 1 ) (283) , possibly via the RB gene product (286) . Indeed, a DNA sequence within the

c-myc gene ( + 20 to +50 from P I ) resembles the RB c-myc was also transcriptionally

control element of the c-fos gene (287) .

inactivated in dibutyryl cAMP-treated HL60 cells, but this mechanism also remains to be elucidated (288) .

Regulation of myc Transcriptional Elongation Regulation at the level of transcriptional elongation has been described in prokaryotic systems , but only recently in the control of eukaryotic genes . This phenomenon plays an important role in the regulation of a number of proto oncogenes , including 293), and

c-myc (289) , L-myc (290) , c-myb (29 1 ) , c-fos (292, c-mos (294) genes, as well as a number of other cellular and viral

genes (289) in which a block to transcriptional elongation has been described. Multiple mechanisms that have been ascribed to attenuation of prokaryotic gene transcription may be relevant to These include

(a)

c-myc transcriptional blockage (289).

association of termination or antitermination factors with

the RNA polymerase II transcriptional complex at specific nucleotide se quences; (b) regions of dyad symmetry followed by polyuridine stretches in the RNA that may or may not associate with accessory factors and impede the progress of the transcription bubble;

(c) sterle interference to polymerase

progression by DNA-binding factors that might also alter the conformation of the DNA template . Truncated first-exon transcripts have not been observed to accumulate in the nucleus or cytoplasm of mammalian cells and appear to be


839

rapidly w asted in the nucleu s . However, Re et al (295) recently identified a 380-nucleotide (nt) truncated human c-myc first-exon transcript, which in creased in quantity upon enhanced c-myc transcriptional blockage. Pausing of


polymerase may be involved in this phenomenon, but most evidence points to premature transcriptional · termination. The regions necessary for transcriptional blockage within c-myc have been defined by a number of studies using the in vitro nuclear run-on assay. Wright & Bishop specified a 1 80-bp region at the 3 ' end of murine exon 1 to be necessary and sufficient to mediate an elongation block within an a-globin gene in HeLa cells (296). Experiments also showed that the c-fos attenuator could replace the c-myc attenuator and mediate a block (297). This region contains GC-rich sequences that have the potential to form a stem-loop structure followed by a T5 tract, and therefore bears a strong architectural resemblance to the rho-independent terminators of prokaryotes . The T5 tract was also observed to be the site of premature termination when the murine c-myc gene was transcribed in Xenopus oocytes (298) . Miller et al reported murine exon 1 sequences were insufficient to block transcripts initiated from the SV40 early and MHC H-2K promoters (299) . The block was restored when myc P2 promoter sequences were introduced in their normal location into the construct (299). myc P2 promoter deletion mutants assayed in HeLa and CV- l identified a nuclear factor-binding site, ME l a l (see Figure 2), required for efficient P2 initiation and blockage (299). Indeed, along with exon 1 downstream sequences , the MEl a l -binding site was alone sufficient to restore transcriptional blockage when inserted in either orientation 3 ' of the MHC H-2K promoter (300) . Interestingly, a sequence bearing a strong re semblance to ME l a l was recently shown to mediate transcription termination of human complement C2 gene transcription (R. Ashfield, P. Enriquez Harris, N. Proudfoot, personal communication). Studies on transcriptional blockage of the human myc gene have revealed many common features with the murine gene. Bentley & Groudine were the first to describe the myc transcriptional block phenomenon with their work on the human myc gene (236) . A 95-bp sequence located 35 bp 5 ' of the exon l Iintron 1 boundary of the human c-myc gene was sufficient to effect pre mature transcriptional termination in Xenopus oocytes when cloned down stream of the HSV tk promoter but not the adenovirus major late promoter (298) . Although these transcripts terminated at one of two thymine-rich sequences , deletion analysis showed that a region with dyad symmetry resem bling a rho-independent terminator caused termination 10--2 0 bp downstream (298) . Linker/scanner and deletion mutagenesis studies in Xenopus oocytes define sequences that appear to be essential for efficient P I elongation between the P2 TATA box and CAP site . Furthermore, these elements only influence PI attenuation when placed downstream of the start site in chimeric

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MARCU ET AL

constructs . In their normal context, these sequences are not required for efficient elongation of P2-initiated transcripts (T. Meulia, T. Krumm, M . Groudine, personal communication). P2 supports transcription by RNA pol II and III; however, pol III transcripts are always blocked near the 3 ' end of exon 1 , while pol II is only partially blocked (30 I , 302) . An in vitro transcription system using purified RNA polymerase I I and polymerase I I I


showed that termination occurred at clusters of 7 Ts in two regions: 20 bp upstream of the exon 1 iintron 1 junction with pol Ill, and 35 bp downstream of exon I with pol II and pol III (303). In a recent report, no premature termination of myc transcription was observed in vitro with HeLa nuclear extracts under standard conditions, but transcripts initiating at myc P2 or the adenovirus MLP prematurely terminated 30 bp downstream of exon 1 in the presence of 400 mM KCI (304). Deletional analysis of the human c-myc gene revealed that as in the murine gene (299), the block to elongation was promoter dependent (239) . Transcripts that initiated at P I did not terminate at the 3 ' end of exon 1 , whereas P2-initiated transcripts either terminated or read through the exon I block signals (239) . c-myc transcription has been shown to be extremely pliable to various growth factors , mitogens , and differentiating agents that may act by altering elongation. Bentley & Groudine observed a rapid, dramatic increase in myc transcriptional blockage upon exposure of HL60 cells to RA (236). The same phenomenon was observed when HL60 cells were treated with DMSO (305), phorbal 1 2 , 1 3-dibutyrate , I ,2-dioconoylglycerol (306) , and probably with 1 ,25-dihydroxyvitamin D3 as well (307, 308). DH site liz upstream of P I decreased i n intensity upon block induction, while D H site I Y within intron 1 increased (236, 305 ) . Enhanced blockage of the murine c-myc gene has been reported for fibroblasts transformed by Abelson murine leukemia virus (A MuLY) (309, 3 1 0) , differentiating MEL cells (292, 3 1 1 , 3 12) , and P 1 9 cells ( 1 1 0) . Induction of the elongation block appears to be a common mechanism for the early downregulation of c-myc during differentiation. Some growth factors and mitogens act by relieving the block to elongation, as seen in pokeweed mitogen (PWM)-treated human tonsillor mononuclear cells; PM A treated human T lymphocytes; mouse spleen lymphocytes and antigen specific T cells exposed to Can A; and EGF-treated mouse fibroblasts (85, 88, 280, 3 1 1 , 3 1 3 , 3 14) . Furthermore, EGF induction of c-myc appears to be cAMP dependent (80) . The block effect also occurred in the absence of de novo protein synthesis , indicating the trans-acting factors required for enhancing blockage already reside in cells, but thcir mechanism(s) of activa tion remain to be elucidated. It also remains to be determined if the cis-acting regulatory elements required for the manifestation of the block are sufficient for its modulation .


84 1


Other Oncoproteins Contribute to myc Transcriptional Regulation Effects on c-myc transcription mediated by a number of oncoproteins have been documented, including v-abl (and possibly other tyrosine kinases) , p53, Jos/jun, adenovirus E1 a, v-erb B, v-raj, early products of polyoma virus, and c-myb. One study demonstrated that the early transforming proteins of polyoma virus induced myc RNA accumulation in BALB/c3T3 cells, but the molecular mechanism was not determined (315). Direct evidence for the induction of constitutive myc transcription was reported in IL-3-dependent FOe-P I murine myeloid cells infected with a temperature-sensitive (ts) v-abl mutant ( 3 1 6). Functional v-abl protein was associated with IL-3 abrogation and deregulated myc transcription , which was manifested by upregulated initiation and abrogation of the first exon transcriptional block. The use of a ts v-abl mutant ruled out a requirement for protein synthesis after v-abl induc tion, implying a direct effect of the v-abl tyrosine kinase. Other tyrosine kinases such as jms, src, and trk also abrogated IL-3 and resulted in con stitutive myc expression, suggesting that a common phosphorylation pathway was involved (316). In contrast to these observations with a myeloid cell line, several independent clones of NIH 3T3 fibroblasts , infected with wild-type v-abl viruses , amplified their c-myc loci and displayed a greatly enhanced transcriptional block (309, 3 10). Together, these observations suggested that effects on myc elicited by an active v-abl tyrosine kinase depend on factors that are likely to be cell-type-specific. Ki-MSV v-raj oncoprotein was found to inhibit the PDGF-induced transcription of myc in BALB/c3T3 cells, while other growth factors on myc-like FGF remained unaffected (3 17). Subsequent to these reports, Evans et al published that the c-myb protein upregulated endogenous myc and an exogenous myc promoter-driven CAT gene in a murine T cell line (3 1 8) . Recently, the same group of investigators have identified multiple c-myb-binding sites upstream of the murine c-myc gene, and found evidence that (a) these c-myb-binding sites are differentially re quired for exogenous myc promoter activation in myeloid and T cell lines; (b) c-myb DNA-binding and trans-activation domains are required for myc pro moter activation (J. Cogswell et aI, personal communication) . A recent study by Zobel et al identified multiple v- and c-myb-binding sites 5 ' of the human c-myc gene, and also observed myb trans-activation of a human myc promoter construct (3 1 9) . Future work will undoubtedly determine whether these effects are mediated by c-myb in normal or transformed cells, and more importantly, their physiological significance for endogenous myc expression. In other work, trans-activation of the human myc gene's P2 promoter by the adenovirus E1 a oncoprotein was shown to require an E2F transcription factor-binding site (GGCGGGAAAA) located between the MElal and


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MEl a2 nuclear factor-binding sites 5' of the P2 initiation site (272, 273 , 320) . However, Ela was also found to inhibit myc transcription (32 1 , 322 ) , again possibly underlying the important contribution(s) o f cellular context. A mutated p53 protein was recently found to trans-activate a human myc P2 promoter-driven reporter gene by an indirect mechanism, while wild-type p53 suppressed a chimeric myclCAT construct, implying that some of the cell growth control attributable to p53 may be mediated via c-myc transcriptional control (323) . Other evidence for the products of proto-oncogenes negatively regulating myc were reported early on by Hay et al (324) , who identified a negative element 3 1 8-343 bp 5 ' of the human myc PI that formed a complex with fosljun heterodimers (324, 325) and more recently also an octamer binding protein (325) . Interestingly , a 13-bp sequence closely resembling an API (josljun complex) transcription factor-binding site, believed to act as a negative regulator of the adipocyte aP2 gene, was identified in this myc negative element (324). Recently, a novel myc RNA species (designated PO I ) �5 kb in size, containing no exon 1 sequences, exon 2, most o f exon 3 , and new exons at its 5 ' and 3 ' ends , was identified in fibroblastic cells transfected with the avi an v-erb B oncogene (Y. Ech el ard K. B . M arc u , E. N. Olson , and A. Nepveu , submitted for publication) . Endogenous c-myc genes express ing PO I RNAs were not rearranged, indicating that PO I production involved dramatic , dominant alterations in c-myc gene regulation, possibly operating at both the transcriptional and posttranscriptional leve1s. POI myc RNAs were found to encode the 65-kDa c-myc-II polypeptide and a novel myc protein of 70 kDa. Cells expressing PO I myc RNAs were malignant in mice. Un fortunately, the relationship between pal myc RNAs and v-erb B remains uncertain because sustained v-erb B expression was not required to maintain POI expression. Considering myc's pivotal role in cellular growth and dif ferentiation pathways , it is not at all unreasonable that regulators of myc may themselves represent the products of other oncoproteins, making these find ings the tip of a very large iceberg. ,

Significance of c-myc Antisense Transcription RNA polymerase II-derived myc antisense transcripts, denoted here as "cym," have been observed in various regions of the human and murine c-myc genes by nuclear run-on assay. However, "cym" transcripts neither accumu lated (236, 309 , 3 1 1 ) nor exhibited any modulation associated with cellular growth states or phenotypes . Cells expressing myc genes fused in a head-to head configuration with Ig genes accumulate "cym Ig" transcripts in addition to aberrant sense myc transcripts (326, 327). Such "cym-Ig" RNAs are found in polyribosomes, but their biological significance remains unknown. There fore , at best, "cym" RNAs remain a molecular oddity awaiting some function al distinction. -


843


Posttranscriptional Control of c-my� Expression Variations in steady-state levels of c-myc polypeptides are only in part attributable to transcriptional modulation. Posttranscriptional control mech anisms play a key role in myc gene regulation, because its mRNAs (328-331) and their encoded polypeptides (33 1 , 332) are normally highly unstable (tl l2 of 10-30 min) and multiple molecular parameters are responsible . Posttrans criptional phenomena strongly contribute to downregulation of myc expres sion in proliferating and differentiating cells. Posttranscriptional mechanisms have been implicated in the rapid depletion of c-myc mRNAs in the later phase of fibroblastic cell responses to growth stimuli; the degree of this effect depends on the cell background and physiological status prior to mitogen addition (3 10) . In several cases , the rapid cessation of de novo protein synthesis has abrogated some of these negative effects, implicating labile factors (328, 338). Remarkably, the overriding means of myc negative control in several types of cells-differentiating F9 teratocarcinoma cells (83 , 1 1 1 , 333, 334), P 1 9 embryonal carcinoma cells induced to yield muscle or neuron al cells ( 1 10), MEL cells induced to become erythrocytes (292, 3 1 1 , 3 1 2) , and BC3H l myogenic cells converting to myoblasts-is posttranscriptional (A. Nepveu, E . Olsen, K. B . Marcu, unpublished). However, in other cases, posttranscriptional effects are only contributory and at times controversial (335-337 , 339 , 340) . Alterations in myc mRNA half-lives are insufficient to explain some of these posttranscriptional phenomena, necessitating the in vocation of more "nebulous" nuclear factors . The degree of posttranscription al regulation of c-myc can also be tissue-specific in vivo, as documented for adult mouse, lymphoid, liver, and brain, and fetal mouse liver development (34 1 ) , N-myc transcripts are also strongly subject to posttranscriptional con trol, given their preferential accumulation in fetal mouse brain, even though the gene is transcribed fairly equivalently in brain , liver, spleen, and placenta (342) . Posttranscriptional phenomena have also been shown to engender positive effects on myc expression. When GO-arrested Chinese hamster lung fibro blasts were treated with growth factors, the dramatic increase in c-myc RNA levels was not accompanied by an appreciable change in transcription (343). The stability of c-myc RNA was altered in EBV-positive BJAB human B lymphoblastoid cells, with the half-life increasing from < 36 min. to > 70 min. (344) . Initial increases in c-myc RNA levels in anti-Ig-treated WEHI.23 1 murine B cells were not entirely due to enhanced transcription (345 , 346) . A transient increase of c-myc expression during the commitment phase of PI9 and MEL cell differentiation has a significant posttranscriptional component ( 1 1 0 , 3 1 1 ) . Posttranscriptional mechanisms are largely respons ible for the dramatic induction of c-myc RNAs in regenerating kidney tissue and mouse liver in vivo (347-349) . Similarly, experiments with a human myc


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gene introduced into FR3T3 rat fibroblasts have revealed that most of the inductive effect of serum was posttranscriptional and prior to mRNA stabilization (350). Stabilization of c-myc RNA is observed in X. laevis oocytes during oogenesis followed by destabilization after fertilization (35 1 ) . Alterations in posttranscriptional control have also been suggested to contrib ute to myc activation in malignancies given that myc transcripts with abnormal structures (absence of first exon and presence of first intron sequences) , produced as a consequence of chromosome translocation, have longer half lives (332, 352-354). Different portions of c-myc transcripts have been implicated as target sites for posttranscriptional control at the RNA level. Pei & Calame (355) reported that myc exon 1 was only able to confer rapid turnover in the context of other myc RNA sequences. Deletionltransfection studies of myc constructs in mouse cells found that exon 1 sequences were insufficient to confer transcript instability, but a 140-bp U-rich sequence in the 3 ' untranslated region (UTR) was sufficient (356). Many c-myc RNAs with truncated or chimeric 3 ' UTRs have greater stability (357) . The responsible target sequences in the myc 3 ' UTR are rich i n As and Us (AUUUA/UUAUUUA) and are involved i n rapid turnover of a number of cellular RNAs (358 , 359) . Surprisingly, site-directed mutagenesis of these 3 ' UTR sequences in murine c-myc (AUUUA to AGGGA) showed no change in the half-life of c-myc mRNAs , implicating yet other ill-defined sequences in the body of the myc transcript (360) . Although the c-myc gene contains two conserved polyadenylation sites, the second of which is used sixfold more frequently, there is no apparent function for their conservation (36 1 ) . c-myc transcript degradation was recently found to occur step-wise in a 3 ' to 5 ' direction: shortening of the poly(A) tail (330, 362, 364-366), followed by removal of the adjacent A+ U-rich sequences, and finally degradation of the body of the message. Using a cell-free mRNA decay system, a ribonucleoprotein that binds the A + U-rich sequence was found to contribute to myc RNA stability (364) . Inhibition of translation dependent myc poly(A) shortening also stabilizes the transcript (366). In apparent contrast to all of these observations, one group reported that de adenylated myc transcripts in cells were more stable (365). Inhibition of translation-dependent poly(A) shortening also stabilizes the transcript, imply ing that a labile protein and/or translation is required for degradation of the transcript (366) . The reasons for multiple sequences possibly providing re dundant regulation remain unclear, but the modes of posttranscriptional con trol could conceiveably differ in various cell types. Evidence for myc translational control has also been reported. The possibil ity that the noncoding first exon modulates the translational efficiency of c-myc RNA was first proposed by Saito et al (367) . However, in vivo transfection studies indicated that the presence of 5 ' UTR sequences did not influence myc mRNA translational efficiency (368). In contrast, in vitro



845

translation assays have shown that full-length c-myc mRNAs have lower translational efficiencies than those lacking exon I (369), and the presence of myc exon I sequences at the 5 ' ends of heterologous transcripts inhibited their in vitro translation (370). Some of these translational inhibitory effects may be due to increased secondary structure (37 1 , 372), and trans-acting factors that melt other cellular RNAs may relieve them (373-375) . Translational effects engendered by myc exon I sequences have been observed in vivo; modulation of myc translational control was reported in X. laevis oocytes and fertilized eggs (376). Here , a 360-nt portion of murine exon I fused 5 ' of the CAT gene decreased translational efficiency, but only at the oocyte stage and not in mature or in vitro fertilized eggs (376). Discordancies between levels of myc RNAs and proteins in tissue culture cells expressing exogenous myc genes implied that translational control may normally operate to keep myc protein quantities in check ( 1 52) . Indeed, one study reported that the induced overexpression of myc polypeptides was toxic in Chinese hamster ovary cells (377) . More recently, one group of investigators has obtained evidence for unusually high levels of myc polypeptide in human myeloma cell lines without concomitant changes in myc mRNAs or polypeptide half-life, imply ing that myc translational control may somehow be circumvented in some malignancies (N. F. Sullivan, personal communication). Clearly, myc trans lational control is both controversial and in need of mechanistic details, which we hope are just over the horizon. MODES OF

myc ACTIVATlON IN MALIGNANCIES

Gene Amplification Amplification of the myc family of oncogenes has been observed late in the progression of a number of human tumors and generally associated with an aggressively malignant phenotype (378-380) . Elevated c-myc expression through gene amplification has been seen in gastric adenocarcinoma cells (38 1 ) , variant small-cell lung carcinoma (SCLC) (3 1 , 382) , glioblastoma (383), carcinoma of the breast (384, 385), colon carcinoma (386), plasma-cell leukemia (387) , promyelocytic leukemia (388, 389), and granulocytic leuke mia (390). The HL60 promyelocytic leukemia cell line is atypical in that c-myc is also amplified in the primary tumor (389). N-myc is amplified in several neuroblastoma cell lines ( 1 7 , 378 , 39 1 ) , retinoblastomas (30), SCLC (2 1 6) , and in one malignant astrocytoma (393). To date, L-myc amplification seems to occur solely in SCLC ( 1 8) .

Proviral Insertion Activation by proviral insertion has been observed for both c- and N-myc. In bursal lymphomagenesis, the c-myc locus was found to be a common integra tion site of avian leucosis virus (ALV), which resulted in 20-100-fold up-


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regulated myc expression (394-396) . Three configurations of ALY insertions , relative to c-myc, have been described: (a) integration upstream o f c-myc coding sequences in the same transcriptional orientation, producing a hybrid mRNA containing proviral sequences fused to c-myc 5 ' sequences, (b) inser tion upstream of c-myc but in the opposite transcriptional orientation, (c) insertion downstream, creating a hybrid transcript with proviral sequences fused to the 3 ' end of c-myc mRNA (394). The mechanism(s) by which proviral insertion enhances c-myc expression appears complex. In the case where the proviral LTR is inserted upstream of c-myc in a positive orientation, c-myc is probably being driven by the viral LTR with its normal transcription al control disrupted. By inserting downstream of c-myc, the provirus could disrupt numerous negative regulatory elements , or the effects of a LTR enhancer could be positively regulating myc expression . The same argument could be made for proviral insertion upstream of c-myc but in opposite orientation . Insertional activation of myc by Moloney murine leukemia virus (Mo MuLY) in mice has been shown to contribute to T cell lymphomagenesis (397-400). In the great majority of tumors exhibiting proviral activation of the c-myc locus, the integration site was upstream of c-myc (or more rarely within exon 1 ) , generally in the opposite transcriptional orientation (397 , 398). In about 35% of T cell lymphomas N-myc was found to be activated by proviral insertion (400) . In contrast to c-myc, the N-myc integration site was limited to a small segment within its 3 ' noncoding sequence, suggesting that this region contains regulatory elements that normally downregulate N-myc expression (400) . Finally, both c- (40 1 ) and N myc (402) were found to be activated by woodchuck hepatitis virus (WHY) in hepatocellular carcinoma. In one study, c-myc was found to be activated by insertion of viral sequences either upstream in the opposite transcriptional orientation, or downstream in the same orientation (40 1 ) . Another study found that the WHY activated N-myc by insertion 3 ' of coding sequences in manner similar to that seen in T cell lymphomas activated by Mo-MuLY (402) . In contrast, human hepatitis B virus integrates into the host genome in a large number of hepatocellular carcinomas , but a single, nonrandom site of integration has not been observed (40 3). -

Chromosomal Translocations Nonrandom chromosomal translocations involving the c-myc locus have been described in a number of tumors . Along with the well-documented myc locus rearrangements in BL and MPC (6-9 , 1 1 , 209, 404, 405), translocations involving c-myc have been described in T cell leukemias (406-408), B cell acute lymphocytic leukemia (409 , 4 10) , and rat immunocytomas (4 1 1 , 4 1 2) .



847

In both MPC and BL, the myc allele, (residing on chromosomes 1 5 and 8 , respectively) is reciprocally translocated to either the immunoglobulin heavy (lgH) or light chain (IgL) loci. Only the translocated myc allele is expressed in these malignancies , with the normal allele being transcriptionally silent (209). This phenomenon strongly implies that myc expression in BL and MPC is abnormal. The most common translocation seen in the neoplasms results in a head-to-head (5 ' -5 ' orientation) of the c-myc and IgH loci. The c-myc coding exons are left intact with the break occurring either 5 ' of exon 1 or within exon 1 or intron 1 . Variant translocations have been described that place one of the immunoglobulin light chain loci several hundred kb 3 ' of c-myc. A number of these distant 3 ' c-myc rearrangements reside at a common locus denoted pvt-l . Large (> 1 2 kb) transcripts originate from pvt-l , and smaller transcripts representing fusions with IgC kappa sequences have been seen in the variant translocations (4 1 3 , 4 1 4) . The normal function of pvt-l and its role in malignancy remain important unanswered queries . Evidence for both lambda and kappa translocations has been seen in BL, but in MPC only kappa translocations have been documented (9). In BL, the majority of translocated myc genes wherein the IgH locus fusions occurred outside of the myc gene accumulated mutations, within the gene's first exon and intron, suggesting that some translocated myc alleles are subjected to a similar if not analogous phenomenon (hypermutation) that mutates rearranged Ig-variable-region gene segments (404) . Exon I mutations have been shown to contribute to the abrogation of RNA polymerase II blockage, thereby resulting in deregulated myc transcription and presumably higher levels of cytoplasmic mRNAs (41 5) . However, other recent data have demonstrated that the presence of such exon I mutations are alone insufficient to abrogate transcription blockage in other B cell backgrounds (239). In one BL cell line harboring a variant translocation of c-myc with the lambda light chain (8:22), a point mutation in intron I abrogated binding of a nuclear protein (277). Five of of seven BL alleles tested for binding of this factor showed mutations that altered its binding capacity (277) . How this intron-binding factor relates to normal c-myc regula tion is not known. c-myc expression in MPC and BL is elevated over that seen in resting B cells, but is not elevated over the level seen in EBV-immortalized B lympho cytes (32 , 239). Expression of myc protein from a non-AUG codon near the 3 ' end of exon 1 has been shown to be absent in some B L lines (32). In the Raji BL line, expression from c-myc' s upstream promoter, PO, was restricted to the translocated allele, although expression from the nontranslocated allele could be induced by TPA while P I and P2 remained silent (41 6) . P3-initiated transcripts were seen from both translocated and nontranslocated alleles (41 6) . Taken together, these observations indicated that PO, P I , P2, and P3 were independently regulated and differentially affected in c-myc deregulation in BL.


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A shift in promoter usage in favor of P I has been consistently reported for translocated alleles in BL and MPC (237, 242). The P2 start site is preferred over P I because its promoter is inherently stronger (299; A . Nepveu, personal communication) . Translocated myc alleles transfected into other cell back grounds transcriptionally recover their normal P I :P2 ratios along with the exon I transcriptional block, suggesting that most of the block originates from P2-initiated mRNAs (239) . Differential myc mRNA stability does not appear responsible for alterations in PI :P2 ratios in neoplasia, since these transcripts retain their inherent instability as seen in normal cells (243). Both cell background and presence of immunoglobulin sequences seem to contribute to the deregulated c-myc transcription. Perhaps immunoglobulin sequences en hance the "accessibility" of the c-myc gene to the transcription machinery, or enhancer elements of the immunoglobulin loci have dominant, differential effects on c-myc expression. However, the intronic enhancers of the IgH and IgL loci are not directly involved with any consistency, suggesting that other

the various Ig loci may be more relevant for activity . In support of this view, a second IgH locus enhancer positioned some distance 3 ' of C-alpha would remain associated with the, majority of the BL T(8; 14) and MPC T( l 2; 1 5) IgH myc rearrangements (41 6a). Furthermore, recent findin gs indicate that the 3 ' C-kappa enhancer may be responsible for the P2 to P I promoter shift in BL variant transloca tions (4 l 6b; G. B omkam m , personal communication) . Since the presence of a translocated c-myc allele is a common feature of BL and MPC, a question arises as to the mechanism of this nonrandom transloca tion . It was proposed early on that the myc locus may be a substrate for the lymphoid cell-specific recombination machinery normally responsible for IgH locus rearrangements during B cell ontogeny (404) . Therefore , when im enhancers located elsewhere in

deregulated myc

-

munoglobul i n loci are actively undergoing i ntramolecular rearrangements ,

be prone to rearrangements with other cellular genes , but direct evidence for the c-myc locus in this phenomenon has never been found. On the contrary , results of experiments to test directly if c-myc was a likely target for Ig CH switch-recombination activity in B cells were negative (404a) . It would be interesting to determine whether RAG] and RAG2 (the proposed recombination activating genes) required for IgV gene assembly pl ay a role in c-myc rearrangements . However, since their cis-acting target sequences are not found near all sites of c-myc translocations , this appears unlikely . Piccoli et al reported the presence of a GAGG sequence near c-myc rearrangements (404b) , but this would seem too simplistic a target site to mediate this phenomen on and again is not found at the site of all myc translocations . Why is the c-myc gene the only oncogene thus far involved in these translocations in BL and MPC? This is likely to be a selected phenomenon, such that nonproductive translocations not leading to a malignant phenotype are lost. Perhaps c-myc resides at a fragile chromosomal site more prone to breakage (404c) . they may also


849

myc INTERACTIONS WITH TUMOR SUPPRESSORS The discovery of tumor suppressor genes, such as the retinoblastoma sus ceptibility gene (PRB) and p53, has led to a great deal of speculation as to the mechanism(s) by which these suppressor genes may be exerting their effect(s) . One could theorize that the product of these genes would interact, either directly or indirectly, with normal cellular genes that are involved in cell growth and/or proliferation. The suppressor genes could regulate the


activity of these growth-associated cellular genes. The loss of function of the proposed tumor suppressors through either a gross deletion or some other mutational event could perturb the normal regulatory loop of these cell cycle-associated genes , such as c-myc, thus leading to inappropriate expres sion and possible tumor progression. Recently, the interaction of c-myc with pRB and p53 has been under scrutiny , and not unexpectedly , the results have proven both titillating and confusing, not to mention controversial . Pietenpol et al (283) have shown that TGF-J3 downregulates c-myc expres sion in mouse keratinocytes in a manner that seems to be mediated by pRB (286). The effect of TGF-{3 could be blocked by the viral proteins HPV- 1 6

E7, adenovirus type 5 E1a , and SV40 large T antigen, when these transform

ing proteins had an intact pRB-binding domain (283) . Adding confusion to this issue is a report showing that c-myc expression is induced, rather than downregulated, in mink lung epithelial cells by TGF-,B (4 1 8) . A recent paper has shown that the pRB protein can bind directly to the c- and N-myc proteins, and a rough map of the binding site on c-myc was given (4 1 9) . There seem to be two pRB-binding sites in the c-myc protein between amino acids numbered 4 1 to 1 7 8 , as a deletion of these residues abrogated binding of c-myc to pRB . Two sites are thought to exist, because pRB binds to mutant c-myc proteins containing deletions of residues 1-74 or 56- 1 03 or 1 09-204 . The domain of pRB that interacts with myc overlaps the binding site for the HPV- 1 6 E7 protein (420), as it is able to compete with c-myc for binding to pRB . E1a has been shown to occupy the same binding site on pRB (42 1 , 422) . Interestingly,

ras oncogene in transformation (see tumorigenesis section) and has now been shown to bind pRB at a site that

c-myc, like £1a, cooperates with an activated

is functionally relevant, as this domain in RB is often deleted or mutated in various human tumors (423-429) . However, in vivo evidence for an interac tion between pRB and c-myc remains to be established. The interaction of c-myc with p53 is not as clearly defined as that with ,oRB . The c-myc protein has not been shown to bind directly to p53 (4 1 9) , though w ild-type p53 has been shown to suppress transcription from a c-myc/CA T construct, while mutant p53 actually induces transcription from these con structs (323) . The effect of p53 on myc is most likely not due to its direct interaction with the c-myc promoter, because a mutant p53 lacking the protein ' s DNA-binding domain retained repressor activity . However, the p53


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polypeptide's nuclear localization signal was essential for its effect on the c-myc promoter (323). Mechanistically, the interaction of myc with antioncogenes is appealing, as pRB could directly bind the c-myc protein, and one could envision a model whereby c-myc would be sequestered from the available active pool owing to its interaction with pRB and its activity effectively neutralized. The loss of this association of c-myc with pRB may lead to overexpression or in appropriate expression of c-myc and contribute to tumor progression. It is critical to determine whether c-myc binds to the underphosphorylated , active, growth-suppressing form of pRB (430--432)-and whether the association of pRB and c-myc renders c-myc inactive, as the pRB-binding domain (4 1 9) maps to one region of c-myc that is required for transformation but is distinct from c-myc' s BR-H-L-H and leucine zipper regions , which are also essential for c-myc's function in transformation (44, 45) . RETROSPECTIVE In considering an appropriate title for our review , we came down to two choices: (a) the one provided, and (b) "Everything you wanted to know about myc but were afraid to ask . " We decided on the former, more conservative choice because myc itself is sufficiently provocative. Data base searches revealed about 3000 citations on myc since its original discovery about 1 2 years ago. If we have neglected to direcly reference a particular laboratory' s contributions, we hope that these can b e found i n an earlier review (of which a number have been cited) . We conclude that myc is a lot of fun to work on, but may be like a puzzle that has one too many solutions . Where does myc go from here? Believe it or not, as Ripley aptly put it once too often, many places! In the coming years , we will likely witness the molecular and bio chemical dissection of the cellular pathways leading to and away from the myc polypeptide. More specifically, we anticipate: (a) a proof of a role for myc in DNA replication, (b) direct demonstrations for c-myc, N-myc, and L-myc heterodimers with max-activating synthetic and natural promoters, which we hope will lead to the elucidation of differential functions for the other mem bers of the myc family, (c) elucidation of the mechanism of myc autoregula tion and its role in the maintenance of cell growth control, (d) identification of the immediate cellular targets of myc that determine cell cycle progression and/or a ceIl's differentiated fate . For diehard myc aficionados who also happen to remain optimistic souls, we predict that the best is yet to come ! ACKNOWLEDGMENTS

We thank our many colleagues who provided their unpublished observations (especially R. N. Eisenman , M. Groudine, A . Nepveu, N . Sullivan, A .


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Kinniburgh, J. Cogswell, J. F. Mushinski, and K . Nilsson) . KBM thanks Margarita Reyes for her heroic efforts in manuscript preparation. SAB and AlP also gratefully acknowledge C. Bossone and 1. Stupakoff for their help and patience. We dedicate this review to the memory of Dr. Paul Fahrlander, for all that he was and all that he might have become .


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c-myc oncoprotein function.

Cellular MYCro economics: Balancing MYC function with MYC expression.

Function of the c-Myc oncoprotein.

Control of c-myc regulation in normal and neoplastic cells.

c-MYC-Making Liver Sick: Role of c-MYC in Hepatic Cell Function, Homeostasis and Disease.

Myc and Max function as a nucleoprotein complex.

MicroRNAs as regulators and mediators of c-MYC function.

Impact of MYC in regulation of tumor cell metabolism.

Transcriptional Regulation of Telomerase Reverse Transcriptase (TERT) by MYC.

Abnormal regulation of the myc gene in myeloid leukemia.

Detecting Aquaporin Function and Regulation.

Regulation of TRPML1 function.

An embryonically expressed gene is a target for c-Myc regulation via the c-Myc-binding sequence.

Transcriptome regulation and chromatin occupancy by E2F3 and MYC in mice.

Melanocortin 1 Receptor: Structure, Function, and Regulation.

DUSP3 phosphatase: structure, function and regulation.

Regulation and function of histone acetyltransferase MOF.

Glucose transporters: structure, function, and regulation.

Topoisomerases and the regulation of neural function.

Acupuncture and regulation of gastrointestinal function.

Mechanosensing and Regulation of Cardiac Function.

Emerging regulation and function of betatrophin.

Adenosine receptors: expression, function and regulation.

Regulation of EGF receptor expression and function.