REVIEW ARTICLE

Journal of

Cellular Physiology

Bioregulation ARTHUR B. PARDEE* Dana Farber Cancer Institute, Boston, Massachussetts

During the 20th century great progress was made in genetics and biochemistry, and these were combined into a molecular biological understanding of functions of macromolecules. Further great discoveries will be made about bioregulations, applicable to scientific problems such as cell development and evolution, and to illnesses including heart disease through defective control of cholesterol production, and to neurological cell-based diseases. The “War Against Cancer” is still far from won. The present generation of scientists can develop clinical applications from recent basic science discoveries. J. Cell. Physiol. 230: 2898–2902, 2015. © 2015 Wiley Periodicals, Inc.

Regulation is at the heart of biology. What are the bioregulatory mechanisms that finely tune and coordinate our cell’s numerous complicated biochemical processes, maintaining constancy of the cell internal environment when external conditions change and a cell differentiates during development? Knowledge of the biochemistry of small molecules in normal cells progressed greatly in the early 1900s. Breakdown of foods including proteins, fats, and starches provided building blocks and the energy-providing molecule adenosine triphosphate (ATP) for synthesis of new cells, including the four nucleotides of DNA, RNA, 20 amino acids of proteins, etc. All of these are rapid reactions that require catalysis by enzymes, shown to be large proteins. Synthesis, functions, and removal of the large molecules, nucleic acids and enzymes, were investigated in the 1950s. This research was named molecular biology. Like all cell functions, these are determined by genetics. DNA is the carrier of heredity, established by Watson and Crick in 1953. The human genome, three billion nucleotide pairs, codes for about 20,000 proteins whose structural information is encoded by only about two percent of the genome. The great majority, previously suggested to be “junk DNA,” is now associated with regulatory and other “administrative” biochemical mechanisms (Pennisi, 2012). Figure 1 illustrates major molecular connections between DNA and the extracellular environment, with enzymes and their separate interacting proteins that provide bioregulations. Elucidation of biological pathways and regulations are investigated by systems biologists (Walhout et al., 2013). New database projects designed to link regulatory DNA to target genes are discussed (Pennisi, 2015). Understanding bioregulation is important for biology, and also for human health. Changed DNA structures, mutations, are found in both protein coding and in non-coding genes of patients with diseases such as cancer. These are numerous and they increase as illness progresses, making effective therapy difficult. Molecular markers, molecules produced by disease cells, are important for finding medical targets and therapies. Bioregulation of Amounts of Enzymes

Biochemistry provides a map showing production and removal of molecules in normal cells, with all roads from highways to footpaths the same. But molecular flow is far greater in some pathways than others, according to cell needs. As an example, very small amount of nicotinamide deamidase are produced by wild type Escherichia coli bacteria, and 10,000-fold greater in a mutant (Pardee et al., 1971). Synthesis of molecules would be wasteful if not controlled by bioregulations. © 2 0 1 5 W I L E Y P E R I O D I C A L S , I N C .

The rate of a reaction depends upon the amount of enzyme. Jacques Monod starting in the 1930s investigated why E. coli produces the enzyme beta-galactosidase only when its substrate sugar lactose is available. The solution is that beta-galactosidase gene expression is blocked by a protein that is released when lactose binds to it, the first repressor protein (Pardee et al., 1956). Molecules in the environment can similarly repress production of enzymes in synthetic pathways, thereby saving biochemical energy. Examples include synthesis of nucleotide building blocks of nucleic acids and of amino acid building blocks of proteins. This bioregulatory mechanism is also found in animals. All the cells inherit the same genes from the sperm- fertilized egg (Gerhart, 2015). Different differentiated cells are produced during development when cells differentiate. What biomechanisms cause them to express different sets of genes? Regulatory protein binding to specific DNA sequences are proposed to deform the double helix structure of DNA (Kim et al., 2013). And epigenetic modifications, small chemical groups that covalently bind to DNA and to attached histone proteins, modulate gene expression (Flintoft, 2007). Early studies are induction of the enzyme penicillinase, which destroys antibacterial penicillin and thereby prevents death of the host bacterium (Pollock, 1957) and receptor-mediated cholesterol homeostasis in mammals, important for heart disease and stroke (Brown and Goldstein, 2009). Oppositely acting processes are found for many bioregulations. An analogy is balancing a bank account with deposits and withdrawals. Protein synthesis is counterbalanced by protein degradation. A protein to be degraded is targeted by binding chains of the small molecule ubiquitin (Komander and Rape, 2012). Proteasomes, large complexes of protease enzymes, then cut the labeled protein into fragments (Finley, 2009). The proteasome inhibitor Bortezomib has clinical applications (Goldberg, 2012).

*Correspondence to: Arthur B. Pardee, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215. E-mail: [email protected] Manuscript Received: 20 May 2015 Manuscript Accepted: 26 May 2015 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 29 May 2015. DOI: 10.1002/jcp.25059

2898

BIOREGULATION

nucleic acids. This pathway is inhibited at the initial enzyme ATCase by its end product, cytidine triphosphate, (CTP). Crystallized ATCase is bioregulated when CTP binds to a site different from its catalytic site and located on a separate regulatory protein. An analogy is a thermostat connected to a furnace. This regulation differs from the classical way to inhibit enzyme-catalyzed reactions, competitive inhibition in which an inhibitor structurally similar to substrate binds to and blocks the catalytic site of the enzyme. Feedback sites have been named allosteric sites (Monod et al., 1963). Allostery also applies to controls of gene expression by repressor proteins that bind to DNA sequences and regulate gene transcriptions (see above), and to neurobiology (Changeux, 2013). Much research has been performed on allostery (Pardee, 2003; Gerhart, 2013). These regulations depend upon modification of the protein 3D conformation caused by inhibitor binding (Lipscomb, 1991). The process is similar to changed protein functioning when phosphate covalently binds to it (Fischer, 1966). Bioregulation of cell proliferation

Fig. 1. A bioregulatory network.

Transfer of genetic information to protein

Genetic information is transferred from nucleotide sequence DNA to the amino acid sequence protein in two steps. The first is transcription, synthesis of messenger RNA (mRNA) copies of the gene’s coding strand. In the second step, translation, mRNA attaches to large ribonucleoproteins named ribosomes. The mRNA’s base sequence binds in ordered sequence other RNAs (transfer RNAs), each with its specific amino acid attached. The ribosome catalyzes incorporation of the amino acid onto the protein’s growing chain. Evidence for mRNA was reported from research showing that nucleic acid precursors are required for protein synthesis (Pardee, 1956). A fourth kind of RNAs are small inhibitory RNAs of about 20 bases have recently been discovered (Darnell, 2011). They pair with complementary base sequences of an mRNA, cause its degradation or prevent translational protein synthesis and have numerous applications to bioregulation (see below). Bioregulation of small molecule production

Cells exist in a dynamic state. They constantly synthesize and degrade macromolecules. If small molecule precursors can be harvested from the environment resources and energy required for synthetic reactions are saved. Bioregulations avoid this loss, by feedback inhibitions of metabolic pathways (Umbarger 1956; Yates and Pardee, 1956). These act at a molecular different level than the repression of enzyme production. Biochemical pathways can proceed through several consecutive enzyme catalyzed steps to produce a small molecule product. For example, about six reactions convert the amino acid aspartate into the pyrimidine building blocks of JOURNAL OF CELLULAR PHYSIOLOGY

Normal animal cells, surrounded by similar cells in vivo, are usually in a density-dependent quiescent state (Go) with unduplicated DNA. Growth factors supplied by blood, stimulate them to proliferate. They pass through the highly organized four stage cycle of cell duplication (Stein and Pardee, 2004). In stage G1 (gap one), enzymes are produced that are needed for DNA synthesis in the second stage S. In third stage G2, the cell prepares for division, and in mitotic stage M, its two DNA copies separate and the cell divides into two daughter cells. This complicated process involves many bioregulations. Growth factors bind to receptor proteins located on the cell membrane and initiate cycling. They are required until the cell passes the regulatory Restriction Point in late G1 phase, and activate phosphorylation of cyclin A protein (Pardee, 1974). And then a sequence of internal protein kinases signal to the nucleus, where they activate transcriptions of enzymes required for DNA synthesis, including a “replitase” multiprotein complex that contains E2F, retinoblastoma-like protein and cdk2 kinase (Reddy, 1980). This also activates gene transcriptions to produce the enzyme thymidine kinase (Dou et al., 1992). Misregulated cells and disease

Current cancer therapies very much need to be improved. Often they delay tumor growth for a few months. There is an enormous literature on potential newer therapies, which cannot even be summarized here. Enzymes and bioregulatory proteins are therapeutic targets of small molecule anti-cancer drugs and antibodies (Mueller, 2015). Hundreds of genes are mutated in cancer cells, causing them to function defectively. Any difference between cancer versus normal cells provides a possible basis for therapy because specificity of activity is essential; treatment must not kill too many of the patient’s normal cells (Weinberg, 2007). Examples cited here are taken from a great many publications on new factors and bioregulatory signaling pathways involved in cancer. KRAS is the most commonly mutated human oncogene, and its function in cancer cells depends on other known molecules. Therapeutic strategy based upon it has only recently been proposed (Azoitei et al., 2012). Wnt mutations are frequent. the secreted Wnt protein’s signaling is dysregulated in many cancers; it increases Wnt beta catenin. Inhibitors of Wnt secretion and interaction with its cell surface receptor (Frizzled) are entering clinical trials. Notch 2/3 is important in stem cell biology; its signaling is

2899

2900

PARDEE

disregulated in several cancers, and its antibody antagonist (Tarextumab) inhibits tumor growth. Deregulated kinases are major factors in cancers. Many therapies based on small molecule inhibitors of protein kinases are being investigated (Zhang et al., 2009). But more than 500 protein kinases are known, so inhibiting only one is difficult and can produce dangerous side effects. The protein kinase C family provides an example. Its 15 members have a variety of functions in regulatory cascades. Numerous allosteric inhibitors of kinases are being investigated, including ones that modify protein kinase activities. AKT is sensitive to an allosteric inhibitor MK-2206, which can enhance antitumor efficacy of other agents (Hirai et al., 2010). Protease inhibitors have similar problems of specificity. Earlier detection of cancer, an approach to better therapy

“Cancers go from bad to worse.” As tumors grow additional mutations produce a diversity of cells, some of which are resistant to therapies. Earlier discovery, therefore, should make treatment more effective. Cancer often is discovered only after a tissue lump, perhaps a billion cells, is found. Information can be obtained from its sliced, stained, and microscopically examined tumor biopsies. But this method can produce false positives, leading to unnecessary therapy (Christiansen et al., 2000). It needs to be supplemented by biochemical confirmations. Total sequencing of an individual’s genome to detect mutations has recently become economically feasible. Genetic predisposition to cancer is revealed by sequencing the DNA of a healthy individual with a family history of cancer. Mutations in the BRCA1 and BRCA2 genes are the most common causes of hereditary breast cancer. Women with BRCA1 mutations have an average 55–65% chance of developing the disease, while the average risk of breast cancer among women with BRCA2 mutations is around 45%. A number of other gene mutations have been associated with hereditary breast cancer, including of the ATM, CHEK2, and TP53 genes. In addition to modest gains in survival, extended therapy with tamoxifen for 10 years compared with 5 years was associated with lower risks of breast cancer recurrence and contralateral breast cancer. But only about 5–10% are inherited; most are not and so cannot be detected. Detections based on faulty bioregulation are beginning to be developed and applied. These could identify cancer before a tumor is physically detected. An approach is to search for cancer-related molecules (biomarkers) in small samples of blood or other body fluids as saliva in which BRCA1 and BRCA2 have been found. An advantage is that the procedure is not invasive (Martin et al., 2010). Bioarrays, sets of biomarkers, provide more definitive information than single biomarkers because of the variability of mutations in cancers. DNA in circulating blood of patients with early malignancies can provide biomarkers. Focus is shifting to mRNA which provides biomarkers for the few percent of the DNA that is expressed (Sager, 1997). Its amplification by the reverse transcriptase polymerase chain reaction provides great sensitivity (Liang et al., 2006). As an example, KRAS detection in blood has high sensitivity and specificity for colorectal cancer (Bettegowda et al., 2014). An approach for detecting cancer is based on small RNAs (Silva and Hannon, 2005; Song et al., 2014). Reappearance of cancer after initial therapy also can be detected with biomarkers in blood. Advances in genomics, proteomics, and molecular pathology have generated many candidate biomarkers with potential clinical value. Their use for cancer staging and personalization of therapy at the time of diagnosis could improve patient care. However, applications from bench to bedside, outside of the research setting, has proved more difficult than might have JOURNAL OF CELLULAR PHYSIOLOGY

been expected. Understanding how and when biomarkers can be integrated into clinical care is crucial if we want to translate the promise into reality (Ludwig and Weinstein, 2005). Effective therapy depends on the genes that are mutated (Beenken et al., 2001). This selection is aided by determinations of biomarkers that determine the type of tumor. For example, three different signaling pathways are responsible for the main kinds of breast cancer. The most frequent (70%) is caused by over production of the estrogen receptor. This hormone’s production stimulates normal breast cell proliferation. It is a lipid that passes through the cell membrane and into the nucleus where it activates genes to produce growth signaling pathways. The second most frequent class of breast cancers is based upon HER2/Neu, a member of the human epidermal growth factor receptor family. In recent years, the protein has become an important biomarker and target of therapy for approximately 30% of breast cancer patients. Signaling through this ErbB family promotes cell proliferation. Amplification or overexpression of this oncogene plays an important role in the development and progression of certain aggressive types of breast cancer. Inside the cell, signaling pathways activated by HER2 include mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K/Akt), phospholipase Cg, protein kinase C (PKC), and signal transducer and activator of transcription (STAT). Triple-negative breast cancer (TNBC) refers to breast cancers that do not mis-express the genes for estrogen receptor (ER), progesterone receptor (PR), or Her2/neu. TBNCs comprise a very heterogeneous group, some of which have poor prognosis. Unknown targets make their treatment difficult (Hanahan and Weinberg, 2000). Expression signatures can also distinguish high- and low-risk cancers (Liu et al., 2007; Cui et al., 2011). Therapeutic bioregulations by inactivation of mRNAs

An mRNAs can be inactivated by base pair binding of a siRNA short sequence (Song et al., 2014). A therapeutic target is indicated when siRNA introduction into a cell inhibits the mRNA function. siRNAs can function as gatekeepers of apoptosis (Subramanian and Steer, 2010). A therapeutic target is indicated when siRNA introduction into a cell inhibits the mRNA function. Problems of specificity can arise from blocking other targets, in part avoided with siRNAs which are synthetic sequences; their non-coding strand is not long enough to bind mRNAs (Sun et al., 2008), Also alternative pathways can make an siRNA ineffective. Therapies based on eliminating dangerous cells

Cancer stem cells (CSC) are newly discovered targets for therapy. After chemotherapy removes the bulk of tumor cells, it provides space for proliferation of rare preexisting CSC and causes tumor recurrence (Li et al., 2015). These cells are functionally similar to the normal embryonic and adult stem cells that produce newly differentiated cells for development and for replacement of lost cells. Stem cells are pluripotent, often quiescent, and their cell cycle is abbreviated (Kapinas et al., 2013). Niches, discrete environments in which stem cells reside, play a dominant part in regulating their behavior and activity (Hsu and Fuchs, 2012). Whether CSCs arise by mutations of stem cells is not clear (Dick, 2009). Breast CSC cells are resistant to conventional chemo and radiotherapy. A new small molecule inhibitor that antagonizes transcription mediated by b-catenin inhibits growth of both bulk and CSC cells (Jang et al., 2015). Metastatic cells are a major cause of cancer death. They escape from a primary tumor into new body locations and

BIOREGULATION

there proliferate to create new tumors. Metastatic cancers are usually incurable; novel therapies are needed to suppress them (Russell and Turnbull, 2014). What altered bioregulations make cells metastatic (Liu et al., 2007; Qiao, 2008; Vira et al., 2012)? One is epithelial–mesenchymal transition (EMT), first recognized in embryogenesis. Mesenchymal cells are loosely connected, mobile, and have invasive capacity. The cells produce N-cadherin, rather than E-cadherin which mediates cell–cell adhesion. They possess heightened amounts of antioxidants that block oxidant therapies through apoptosis in p53-minus cells. IL-6 like cytokines are gene transcription activators that drive the cells to commence cell proliferation (Watson, 2013). A bioregulated programmed cell death mechanism named apoptosis is opposite to cell proliferation (Indran IR, et al., 2011). It is a major mechanism for suppressive death of cancer cells. It is activated by DNA damage (Linke et al., 1996). Mutations that inactivate apoptotic genes permit cancer cells to survive, a major cause of patient death. p53 protein, named Guardian of the Genome, is a tumor suppressor. It causes apoptosis and removes damaged potentially cancerous cells. DNA damage can cause intracellular organelles named mitochondria to release the small protein cytochrome C, which activates a complex apoptosis pathway involving caspase proteases. Mitochondria are involved in control of apoptosis (Inthrani et al., 2011). These organelles contain 37 genes coded in 16,600 base pairs of DNA. They supply energy to the cell, producing ATP via oxidations are new targets for therapy. Perhaps the earliest proposal about the cause of cancer is the Warburg hypothesis of modified ATP production (Vadlakonda, 2013). Mitochondrial disfunction in breast cancer cells is involved in tumor growth, and for chemo-prevention (Sanchez-Alvarez et al., 2013). The small molecule Metformin blocks stage 2 oxidative phosphorylation by mitochondria, and it selectively kills mesenchymal cancer cells. The natural product b-lapachone and its derivatives prevent ATP production and stop growth of tumors, although they soon reappeared (Huang et al., 2012; Chakrabarti et al., 2015). Pyrimidines have a role in mitochondrial metabolism, possibly an allosteric function. Deficient pyrimidine biosynthesis might cause a strong p53 response in cells with impaired mitochondrial respiration, or from inhibition of the electron transport chain III pyrimidine complex. Literature Cited Azoitei N, Hoffmann CM, Ellegast JM, Bail CR, Obermeyer K, Gobele U, Koch B, Faber K, Genze F, Schrader M, Ketler HA, Dohner GH, Chiosis G, Gilmm H, Frohling S, Scholl C. 2012. Targeting of KRAS mutant tumors by HSP60 involves degradation of STK33. J Exp Med 209:697–711. Beenken SW, Grizzle WE, Crowe R, Conner MG, Weiss, HL, Sellers MT, Krontiras H, Urist MM, Bland KI. 2001. Molecular biomarkers for breast Cancer prognosis: Coexpression of c-erbB-2 and p53. Ann Surg 233:630–638. Bettegowda C, Sausen M, Leary RJ, Kinde I, Wang Y, Agrawal N, Bartlett BR, Wang H, Luber B, Alani RM, Antonarakis ES, Azad NS, Bardelli A, Brem H, Cameron JL, Lee CC, Fecher LA, Gallia GL, Gibbs P, Le D, Giuntoli RL, Goggins M, Holdhoff M, Hong S-M, Jiao Y, Juhl HH, Kim JJ, Siravegna G, Laheru DA, Lauricella C, Lim M, Lipson J, Kazue S, Marie N, Netto GJ, Oliner KS, Olivi A, Olsson L, Riggins G, Sartore-Bianchi A, Schmidt K, Shih LM, Oba-Shinjo SM, Siena S, Theodorescu D, Tie J, Harkins TT, Veronese S, Wang T-L, Weingart JE, Wolfgang CL, Wood LD, Xing D, Hruban RH, Wu J, Allen PJ, Schmidt CM, Choti MA, Velculescu VE, Kinzler KW, Vogelstein B, Papadopoulos N, Diaz, Jr. LA. 2014. Detection of circulating tumor DNA in early- and late-stage human malignancies Sci Transl Med 6:224ra24. Brown MS, Goldstein JL. 2009. Cholesterol feedback: From Schoenheimer’s bottle to Scap’s MELADAL. J Lipid Res S15–S27. Chakrabarti G, Gerber DE, Boothman DA. 2015. Expanding antitumor therapeutic windows by targeting cancer-specific nicotinamide adenine dinucleotide phosphate–biogenetic pathways. Clin Pharmacol 7:57–68. Changeux JP. 2013. The concept of allosteric interaction and its consequences for the chemistry of the brain. J Biol Chem 28826969–26986. Christiansen CL, Wang F, Barton MB, Kreuter W, Elmore JG, Gelfand AE, Fletcher SW. 2000. Predicting the cumulative risk of false-positive mammograms. JNCI 92:1657– 1666. Cui J, Li F, Wang G, Fang X, Puett JD, Xu Y. 2011. Gene-expression signatures can distinguish gastric cancer grades and stages. PLOS ONE 6:e17819. Darnell J. 2011. RNA life’s indispensible molecule. Cold Spring Harbor Press. Cold Spring Harbor, New York.

JOURNAL OF CELLULAR PHYSIOLOGY

Dick JF. 2009. Looking ahead in cancer stem cell research. Nat Biotechnol 27:44–66. Dou QP, Markell PJ, Pardee AB. 1992. Thymidine kinase transcription is regulated at G1/S phase by a complex that contains retinoblastoma-like protein and a cdc2 kinase. Proc Natl Acad Sci USA 89:3256–3260. Finley D. 2009. Recognition and processing of ubiquitin-protein conjugates by the proteasome. Ann Rev Biochem 78:477–513. Fischer E. 1966. Relationship of structure to function of muscle phosphorylase. Fed Proc 25:1511–1520. Flintoft L. 2007. An eXpanding view of DNA methylation. Nat Rev Genet 8:248–251. Gerhart J. 2015. Cells, embryos, and evolution. 1998. Blackwell Science, Malden, MA. Gerhart J. 2013. From feedback inhibition to allostery: The enduring example of aspartate transcarbamoylase. FEBS J 281:612–620. Goldberg AL. 2012. Development of proteasome inhibitors as research tools and cancer drugs. J Cell Biol 199:583–588. Hanahan D, Weinberg RA. 2000. The hallmarks of cancer. Cell 100:57–70. Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi K, Tsujioka K, Ueno Y, Hatch H, Majumder P, Pan B-S, Kotani H. 2010. MK-2206, an allosteric Akt inhibitor enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 9:1956–1957. Hsu Y-C, Fuchs E. 2012. A family business: Stem cell progeny join the niche to regulate homeostasis. Nat Rev Mol Cell Biol 13:103–114. Huang X, Dong Y, Bey EA, Kilgore JA, Bair JS, Li LS, Patel M, Parkinson E, Wang Y, Williams NS, Gao J, Hergenrother PJ, Boothman DA. 2012. An NQO1 substrate with potent anti-tumor activity that selectively kills by PARP-induced programmed necrosis. Cancer Res 72:3038–3047. Iliopoulos D, Hirsch HA, Struhl K. 2011. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 71:3196–3200. Indran IR, Tufo G, Pervaiz S, Brenner C. 2011. Recent advances in apoptosis, mitochondria and drug resistance in cancer cells. Biochim Bioph Acta 1807:737–745. Jacob F, Monod J. 1961. Genetic regulatory mechanisms in the synthesis of proteins. J Mol Biol 3:318–356. Jang GB, Hong IS, Kim RJ, Li SY, Park SJ, Lee ES, Park JH, Yun CH, Chung JU, Lee KJ, Lee HY, Nam JS. 2015. Wnt/b-catenin small molecule inhibitor CWP232228 preferentially inhibits the growth of breast cancer stem-like cells. Cancer Res 75:1961–1702. Kapinas K, Grandy R, Ghule P, Medina R, Becker K, Pardee AB, Zaidi SK, Lian J, Stein J, Van Wijnen A, Stein G. 2013. The abbreviated pluripotent cell cycle. J Cell Physiol 228:9–20. Kim S, Brostromer E, Xing D, Jin J, Chong S, Ge H, Wang S, Gu C, Yang L, Yi Q, Y Gao, Su X, Sun Y, Xie S. 2013. Probing allostery through DNA. Science 339:816–819. Komander D, Rape M. 2012. The ubiquitin code. Ann Rev Biochem 81:203–229. Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, Leggett D, Li W, Pardee AB, Li CJ. 2015. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci USA 112:1839–1844. Liang P, Meade JD, Pardee AB. 2006. Differential display methods and protocols. 2nd Ed. Humana Press, Inc. Totowada, N. J. 02512. Linke SP, Clarkin KC, Di Leonardo AD, Tsou A, Wahl GM. 1996. A reversible, p53-dependent G0/G1 cell cycle arrest induced by ribonucleotide depletion in the absence of detectable DNA damage. Genes Dev 10:934–937. Lipscomb WN. 1991. Structure and function of allosteric enzymes. Biochem Mol Biol 2:1–15. Liu R, Wang X, Chen G, Dalerba P, Gurney A, Hoey T, Sherlock G, Lewicki J, Shedden K, Clarke MF. 2007. The prognostic role of a gene signature from tumorigenic breast-cancer cells. NE J Med 356:217–226. Ludwig JA, Weinstein JN. 2005. Biomarkers in cancer staging, prognosis and treatment selection. Nat Rev Cancer 5:845–856. Martin KJ, Fournier MV, Reddy GP, Pardee AB. 2010. A need for basic research on fluid-based early detection biomarkers. Cancer Res 70:5203–5206. Monod J, Changeux J-P, Jacob F. 1963. Allosteric proteins and cellular control systems. J Mol Biol 6:306–329. Mueller KL. 2015. Realizing the promise. Immunotherapy against cancer. A set of reviews. Science 348:55–86. Pardee AB. 1956. Nucleic acid precursors and protein synthesis. Proc Natl Acad Sci USA 40:263–270. Pardee AB, Jacob F, Monod J. 1956. The genetic control and cytoplasmic expression of “inducibility” in the synthesis of b-galactosidase. J Mol Biol 1:165–178. Pardee AB, Benz EJ, Jr., St. Peter DA, Krieger JN, Meuth M, Trieshmann HW, Jr. 1971. Hyperproduction and purification of nicotinamide deamidase, a microconstitutive enzyme of Escherichia coli. J Biol Chem 246:6792–6796. Pardee AB. 1974. A restriction point for control of normal animal cell proliferation. Proc Natl Acad Sci USA 71:1286–1290. Pardee AB. 2003. Beginnings of feedback inhibition, allostery, and multiprotein complexes. Gene 121:17–23. Pennisi E. 2012. ENCODE project writes eulogy for junk DNA. Science 337:1159–1161. Pennisi E. 2015. New database links regulatory DNA to its target genes. Science 348:618– 619. Pollock MR. 1957. The activity and specificity of inducers of penicillinase production in Bacillus cereus, strain NRRL569. Biochem J 66:419–428. Qiao M. 2008. Metastasis and AKT activation. Cell Cycle 7:2991–2996. Reddy GPV. 1980. A “replitase” multiprotein complex for DNA synthesis contains E2F, retoinoblastoma-like protein, and cdk2 kinase, and binds to the thymidine kinase gene promoter. Proc Natl Acad Sci USA 77:3312–3316. Russell O, Turnbull D. 2014. Mitochondrial DNA disease-molecular insights and potential routes to a cure. Exp Cell Res 325:38–43. Sager R. 1997. Expression genetics: Shifting the focus from DNA to RNA. Proc Nat Acad Sci USA 94:952–955. Sanchez-Alvarez R, Martinez-Outschoorn UE, Lamb R, Hulit J, Howell A, Gandara R, Sartini M, Rubin E, Lisanti MP, Sotgia F, 2013. Mitochondrial dysfunction in breast cancer cells prevents tumor growth: Understanding chemoprevention with metformin. Cell Cycle 12:172–182. Silva JM, Hannon G. 2005. Second generation shRNA libraries covering the mouse and human genomes. Nat Genet 37:1281–1288. Song R, Liu Q, Hutvagner G, Nguyen H, Ramamohanarao K, Wong L, Li J, 2014. Rule discovery and distance separation to detect reliable miRNA biomarkers for the diagnosis of lung squamous cell carcinoma. BMC Genom 15:S16. Stein GS, Pardee AB. 2004. Cell cycle and cell growth control. Biomolecular regulation and cancer. Hoboken, N. J.: John Wiley & Sons. Subramanian SJ, Steer CJ. 2010. MicroRNAs as gatekeepers of apoptosis. J Cell Physiol 223:289–298.

2901

2902

PARDEE

Sun X, Rogoff HA, Li CJ. 2008. Asymmetric RNA duplexes mediate RNA interference in mammalian cells. Nat Biotech 26:1379–1382. Umbarger HE. 1956. Evidence for a negative-feedback mechanism in the biosynthesis of isoleucine. Science 123:848. Vadlakonda L. 2013. Did we get Pasteur, Warburg, and Crabtree on a right note? Front Mol Cell Oncol 10:3389. Vira D, Basak SK, Veena MS, Wang MB, Batra RK, Srivatsan ES. 2012. Cancer stem cells, microRNAs, and therapeutic strategies including natural products. Cancer Metastasis Rev 31:733–751.

JOURNAL OF CELLULAR PHYSIOLOGY

Walhout AJM, Vidal M, Dekker J. 2013. Handbook of systems biology—Concepts and insights. Waltham, MA: Academic Press. Watson JD. 2013. Oxidants, antioxidants, and the current incurability of metastatic cancers. Open Biol 3:120144. Weinberg RA. 2007. The biology of cancer. New York, N. Y.: Garland Science. Yates RA, Pardee AB. 1956. Control of pyrimidine biosynthesis in Escherichia coli by a feedback mechanism. J Biol Chem 221:757–770. Zhang J, Yang PL, Gray NS. 2009. Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9:28–38.

Bioregulation.

During the 20th century great progress was made in genetics and biochemistry, and these were combined into a molecular biological understanding of fun...
275KB Sizes 4 Downloads 6 Views

Recommend Documents