Symposium Pathobiology 1992;60:278-283
C. Parker G. V. Sherbet Cancer Research Unit, University of Newcastle upon Tyne Medical School, Newcastle upon Tyne, UK
Modulation of Gene Function by Retinoic Acid
KeyWords Retinoic acid Target genes Growth factors Metastasis
Introduction Recent years have seen a very rapid growth in the liter ature relating to the biological actions of retinoids. Reti noic acid (RA) is now known to modulate gene expression and control a variety of biological pathways of cell growth, differentiation, pattern formation, and tumour development and progression. The purpose of this review is to complement the coverage of aspects discussed in sis ter reviews published in this issue of Pathobiology. by tra versing the molecular biological areas of modulation of gene function by retinoic acid.
ments (RAREs) have been identified in (i-retinoic acid receptor [5, 6] and the laminin B1 genes [7], The thyroid hormone (3,5,3'-L-triiodolhyronine, T 3) receptor has also been identified as a member of the nuclear receptor super family. The T 3 receptor also regulates gene transcription by means of specific responsive elements [8, 9], It has been reported that RA and T 3 might be regulating gene transcription through a common response element [ 10, 11], Furthermore, Glass et al. [12] found that RA and T 3 receptors can form heterodimers.
Gene Targets for Activated RA Receptors
The regulation of target genes by steroid hormones is mediated by specific receptors which recognise defined DNA sequences and modulate gene transcription [1, 2], The receptors which mediate the biological actions of RA have been isolated. Four related retinoic acid receptors (RAR), viz. RAR-a, RAR-p, RAR-y and hRXR-a, have been described [3a], They belong to the steroid/thyroid hormone receptor superfamily [3b, 4] because of their structural similarity to the latter. These receptors are thought to act as transcription factors following activation by the binding of the ligand. Retinoic acid response ele
Received: August 12. 1991 Accepted: August 12. 1991
Hox Gene Expression LaRosa and Gudas [13] have identified an early direct target for RA, viz. the ERA-1 gene which shows a rapid and protein-synthesis-independent induction during tcratocarcinoma stem cell differentiation. The raised ERA-1 mRNA levels associated with RA exposure are not attrib utable to a stabilisation of the message and by implication the response is believed to occur at the transcriptional level [14], These authors also reported that the RAinduced 2.2-2.4 kilobase ERA-1 RNA consists of two alternately spliced transcripts for a homeobox-containing protein and one lacking the homeobox. The homeobox containing protein of the Drosophila gene, engrailed, and
C. Parker Cancer Research Unit University o f Newcastle upon Tyne Medical School Newcastle upon Tyne NE2 4HH (UK)
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RA Receptors and Transcriptional Regulation
The MK Gene Another genomic target which has been identified in the early stages of RA-induced differentiation of em bryonal carcinoma is the MK gene. Kadomatsu et al. [22] reported that this gene is transiently expressed in em bryonal carcinoma cell differentiation and in the mid-ges tation stage of mouse embryonic development. That the MK is an RA-responsive gene is indicated by the work of Huang et al. [23], who showed that the expression of the gene is dependent upon RA concentration, and with drawal of RA results in a reduction of MK transcripts. The MK gene transcripts are heterogeneous and three subclones, MK1, MK2 and MK3, of the MK transcripts could be differentiated. These clones differed in the 5'untranslated region. The MK2 type RNA was the major component in RA induced differentiation [24], The MK gene product has been found to possess heparin-binding activity and there are suggestions that this might be a growth factor or one that regulates the actions of growth factors [25].
Regulation of Hormone and Growth Factor Genes Growth factors and hormones and their receptors play a major role in cell proliferation, growth and differentia tion as well as in neoplastic growth and its progression to the metastatic state. Retinoids are powerful growth inhib itory agents [26-28], although under certain circum stances a growth stimulation might occur. Indeed, mem bers of the steroid hormone receptor family as well as RA receptors achieve transcriptional control by inductive as well as inhibitory mechanisms. It is logical, therefore, that the effects of RA and its receptors on genes coding for hormones and growth factors should have been the sub ject of considerable investigation in the past few years. RARs activated by related ligands regulate the tran scription of specific genes by binding to identifiable response elements occurring in the promoter regions of these genes. A high degree of homology has been found between RAREs and the T3 receptor binding DNA do main (the TRE, thyroid hormone responsive element). In fact, genes which contain the TRE can be transactivated by RARs [11], In the pituitary cell line GH1, T 3 stimu lates growth hormone production. These cells also re spond to RA, which stimulates growth hormone produc tion on its own as well as synergistically with T 3 and dexamethasone. The RA-receptor complexes are thought to interact with DNA sequences to alter the expression of the growth hormone gene [29]. The polypeptide growth factors, such as the epidermal growth factor (EGF) and transforming growth fractor alpha (TGF-a), stimulate growth, whereas TGF-p can either stimulate or inhibit growth depending upon the tar get cell type. The interaction of RA in growth control by these growth factors has provided much information per taining to the control of cellular proliferation and growth in normal and neoplastic systems. Growth promoters such as EGF, the phorbol ester tumour promoter TPA and second messengers such as cyclic AMP are positive transcriptional regulators of the EGF receptor promoter [30], The promoter of the erhB2/neu gene, which codes for a tyrosine kinase growth factor receptor, is also positively regulated by these agents [31], although a specific ligand for this receptor is yet to be discovered. On the other hand, activated T 3and RA receptors both inhibit the EGF receptor and the erbB2 gene [32], In HL-60 promyelocytic leukaemia cells, RA inhibits proliferation in a dose-dependent fashion and induces granulocytic differentiation. According to Falk et al. [33] this appears to be the result of an enhanced expression of TGF-Pi receptors on the cell surface, together with an
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the homeobox of hox 1.5 mouse show sequence specific DNA binding in vitro [15, 16], which suggests that ho meobox containing proteins may regulate specific sets of genes. It has been suggested, therefore, that the in vivo and in vitro effects of RA might involve homeobox con taining genes, of which ERA-1 is a prime example. Other authors have described the activation of hox genes related to exposure of embryonal carcinoma cells in culture to RA. but not related to the process of differentiation [17, 18]. Stornaiuolo et al. [19] studied the expression of 33 human homeobox (hox) genes belonging to four hox loci in the embryonal carcinoma NT2/D1 cells. Whereas none of these genes were normally expressed in N T2/D 1 cells, 22 were induced to express upon treatment with RA. The 1 1 hox genes which could not be induced were located in the 5' region of the hox"loci. Furthermore, both this study by Stornaiuolo et al. [ 19] and the previous one by Breier et al. [20] have indicated that the homeobox genes are differ entially expressed in response to RA. The expression of these genes could conceivably determine the activation of regionally important genes, such as those involved in pat tern formation. Chisaka and Capecchi [21] have demon strated quite convincingly that hox genes also regulate vertebrate development and that spatial and temporal dif ferentiation may be determined by the ‘positional infor mation’ flowing from the different combinations of hox gene expression.
Regulation of Genes Coding for Proteinases One of the important properties of TNF is its ability to degrade the extracellular matrix. Collagenase and stromelysin are two prominent metalloproteinases taking part in the degradation of the extracellular matrix [41,42]. It has been reported that TNF-a increases collagenase produc tion by human synovial cells and skin Fibroblasts [43]. Chua and Chua [44] found that the cytokine induced a 10-fold increase in collagenase gene transcripts following treatment of skin fibroblasts by TNF. It also induced the activity of tissue inhibitor of metalloproteinases (TIMP). Ito et al. [45] have also reported that collagenase and stromelysin are induced by TNF in a dose-dependent fashion. TIMP is induced by TNF at low concentrations but the increased synthesis of TIMP is inhibited at high concentration ranges of TNF. The induction of both the enzyme and the inhibitor has been reported in the case of other growth factors such as interleukin I (IL-1) and growth promoters like TPA [46], It may be that there is regulation of the expression of collagenase and TIMP which is dependent upon the endogenous levels of TNF, which in its turn may be controlled by RA. Strickland and Mahdavi [47] observed that F9 embryonal carcinoma cell differentiation following exposure to RA was accompa nied by increased synthesis and secretion of plasminogen activator. Wang and Gudas [48] have shown that one of
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the cDNA clones expressed abundantly in these cells after RA exposure codes for a proteinase inhibitor belonging to the serine proteinase inhibitor family. Thus a co-ordi nated regulation of expression of both proteinases and their inhibitors might not be an uncommon phenome non. The regulation of the genes coding for collagenase and stromelysin has been studied recently. Lafyatis et al. [49] showed that IL-1 enhances collagenase secretion by in creasing the steady state levels of the collagenase gene transcripts. RA has the opposite effect. Both the negative and positive regulatory effects have been found to be mediated by the TPA-responsive elements. The transcrip tion factor AP-1 binds to the TPA-responsive element and increases transcription. The AP-1 itself is a hetero dimer complex consisting of fos and jun proteins. Both IL-1 and TPA (which is itself capable of inducing the col lagenase gene) induce these early response genes. How ever, RA down-regulates only the fos but not th ajun onco gene, suggesting that RA might inhibit transcription of the collagenase gene by inhibiting fos expression. Expression of the stromelysin gene is also inhibited by RA and this effect is mediated by a 25 Kb 5'-flanking DNA sequence of the stromelysin gene which includes the AP-1 binding site [50].
Modulation of Metastasis-Associated Genes Retinoic acid has been shown consistently to inhibit the process of cancer invasion and metastasis [51-54], The inhibition of cellular invasion is accompanied by a decreased expression of proteolytic enzymes such as collagenases and plasminogen activator which enable the deg radation of the extracellular matrix components [51, 52], RA has also been known to induce the synthesis of extra cellular matrix proteins such as laminin and collagen IV and higher steady state levels of mRNA coding for these proteins are evident in cells following RA treatment [55], These alterations can affect the adhesive abilities of tumour cells and as a consequence alter the metastatic behaviour of tumour cells [56], Several genes are known to be differentially expressed in normal cells and their malignant counterparts. Among these are genes coding for fibronectin [57] and the WDNM1 and WDNM2 genes [58, 59], These genes are expressed at a reduced level, while the proteinase transin (stromelysin) gene is expressed more abundantly in malig nant tumours [60], A metastasis suppressor gene, the nm23. has been described in murine melanomas [61,62],
Modulation of Gene Function by Retinoic Acid
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enhanced expression of TGF-(3i gene. TGF-P and RA act synergistically to inhibit phorbol ester induced cellular transformation. This is due in part to modulation of the TGF-P receptor expression [34], In cultured kératino cytes, the inhibition of DNA synthesis by RA is accompa nied by an increased expression of TGF-P2. The latter is secreted in the active form and can then bind to surface receptors [35]. Glick et al. have also shown that anti-TGFP2 antibodies abrogate the ability of RA to inhibit DNA synthesis. Tumour necrosis factor (TNF) is a cytokine released by macrophages and monocytic cells stimulated by lipopoly saccharide [36], TNF is highly cytotoxic, causes necrosis of solid tumours [36, 37] and inhibits the growth of both normal and tumour cells in vitro [38, 39], The release of TNF by LPS stimulation of peripheral blood monocytes has been found to require the presence of endogenous RA. However, neither the intracellular levels of TNF nor TNF mRNA were affected by the removal of RA [40]. This sug gests that RA may not be directly involved with the posi tive regulation of the TNF gene.
A dominant metastasis gene, mlsl, has been reported which is highly expressed in high metastasis murine tumours and human tumours grown as xenografts [63, 64], Thus there are a number of candidate metastasis genes, i.e. those postulated to be the determinants of the metastatic behaviour, as well as target genes, such as the laminin, collagenase, and stromelysin genes, which might control specific events in the metastatic cascade. There is a considerable body of evidence which sup ports the association between the putative candidate me tastasis genes such as the mtsl and the nm23 but it ought to be emphasised that the evidence is mainly empirical. Recently Parker et al. [54] have modulated the metastatic behaviour of the B16 murine melanoma variants using RA and have examined whether the expression of these genes is also concomitantly modulated. They have re ported that RA decreased lung colonisation by the high metastasis variant BL6 and MLS melanomas and in par allel down-regulated the mtsl gene. The expression of mn23 did not show an inverse relationship to the meta static potential of the melanoma variants. Nevertheless, RA upregulated its expression, albeit not in a consistent fashion. Parker et al. [54] also found that melanocyte stimulating hormone (MSH) increased lung colonisation by the low metastasis variant B16-F1, with a parallel increase in m lsl expression. MSH did not alter the expression of the nm23 gene. The patterns of changes of expression were not always consistent with RA treatment, but the pattern of changes in the ratios of nm23 and mlsl expression has suggested that these two genes are co-ordi nately regulated by RA. There were substantial differ ences between the variant cell lines in their transcrip tional regulation of the genes, i.e. both genes appear to be transcriptionally less responsive in the low malignancy variant than in the high metastasis variant. In addition, it appeared that the nm23 gene is transcriptionally more responsive than the mlsl in the high metastasis variant.
The effects of these two genes on the expression of the phenotypic behaviour of tumour cells may be comple mentary and, whereas in low metastasis variants their reg ulation may be closely interlinked, in high metastasis variants there could be an uncoupling of the mechanisms of regulation. We are currently elucidating the signal transduction pathways by which MSH and RA regulate the expression of mlsl and nm23 genes and how these pathways are interlinked. MSH is known to stimulate adenylate cyclase (AC) activity and increase the intracellular levels of cAMP. This in turn will activate the protein kinase A (PKA) signal transduction pathway. A consequence of this is a transient increase in the expression of the early response genes c-fos and junB [Parker et al., unpubl. observations] which code tor the transcription activating protein heterodimer API. Increased mtsl expression in the low metastasis variant B16F1 after treatment with MSH may be via activation of these genes. The 3' region of the gene contains an API-like sequence which is homologous to an API enhancer element in the 3' region of the chick (i-globin gene. Retinoic acid, on the other hand, has been shown to lower the basal levels and MSH stimulated AC activity [65] and the down-regulation of mtsl expression in the high metastasis variant BL6 and ML8 melanomas by RA may be due to a reduction in AC activity and subsequent PKA mediated signal transduction.
Acknowledgments This work was supported by grants from the North of England Cancer Research Campaign and the Tom Berry Memorial Fund.
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C. Parker G. V. Sherbet Cancer Research Unit, University of Newcastle upon Tyne Medical School, Newcastle upon Tyne, UK
Modulation of Gene Function by Retinoic Acid
KeyWords Retinoic acid Target genes Growth factors Metastasis
Introduction Recent years have seen a very rapid growth in the liter ature relating to the biological actions of retinoids. Reti noic acid (RA) is now known to modulate gene expression and control a variety of biological pathways of cell growth, differentiation, pattern formation, and tumour development and progression. The purpose of this review is to complement the coverage of aspects discussed in sis ter reviews published in this issue of Pathobiology. by tra versing the molecular biological areas of modulation of gene function by retinoic acid.
ments (RAREs) have been identified in (i-retinoic acid receptor [5, 6] and the laminin B1 genes [7], The thyroid hormone (3,5,3'-L-triiodolhyronine, T 3) receptor has also been identified as a member of the nuclear receptor super family. The T 3 receptor also regulates gene transcription by means of specific responsive elements [8, 9], It has been reported that RA and T 3 might be regulating gene transcription through a common response element [ 10, 11], Furthermore, Glass et al. [12] found that RA and T 3 receptors can form heterodimers.
Gene Targets for Activated RA Receptors
The regulation of target genes by steroid hormones is mediated by specific receptors which recognise defined DNA sequences and modulate gene transcription [1, 2], The receptors which mediate the biological actions of RA have been isolated. Four related retinoic acid receptors (RAR), viz. RAR-a, RAR-p, RAR-y and hRXR-a, have been described [3a], They belong to the steroid/thyroid hormone receptor superfamily [3b, 4] because of their structural similarity to the latter. These receptors are thought to act as transcription factors following activation by the binding of the ligand. Retinoic acid response ele
Received: August 12. 1991 Accepted: August 12. 1991
Hox Gene Expression LaRosa and Gudas [13] have identified an early direct target for RA, viz. the ERA-1 gene which shows a rapid and protein-synthesis-independent induction during tcratocarcinoma stem cell differentiation. The raised ERA-1 mRNA levels associated with RA exposure are not attrib utable to a stabilisation of the message and by implication the response is believed to occur at the transcriptional level [14], These authors also reported that the RAinduced 2.2-2.4 kilobase ERA-1 RNA consists of two alternately spliced transcripts for a homeobox-containing protein and one lacking the homeobox. The homeobox containing protein of the Drosophila gene, engrailed, and
C. Parker Cancer Research Unit University o f Newcastle upon Tyne Medical School Newcastle upon Tyne NE2 4HH (UK)
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RA Receptors and Transcriptional Regulation
The MK Gene Another genomic target which has been identified in the early stages of RA-induced differentiation of em bryonal carcinoma is the MK gene. Kadomatsu et al. [22] reported that this gene is transiently expressed in em bryonal carcinoma cell differentiation and in the mid-ges tation stage of mouse embryonic development. That the MK is an RA-responsive gene is indicated by the work of Huang et al. [23], who showed that the expression of the gene is dependent upon RA concentration, and with drawal of RA results in a reduction of MK transcripts. The MK gene transcripts are heterogeneous and three subclones, MK1, MK2 and MK3, of the MK transcripts could be differentiated. These clones differed in the 5'untranslated region. The MK2 type RNA was the major component in RA induced differentiation [24], The MK gene product has been found to possess heparin-binding activity and there are suggestions that this might be a growth factor or one that regulates the actions of growth factors [25].
Regulation of Hormone and Growth Factor Genes Growth factors and hormones and their receptors play a major role in cell proliferation, growth and differentia tion as well as in neoplastic growth and its progression to the metastatic state. Retinoids are powerful growth inhib itory agents [26-28], although under certain circum stances a growth stimulation might occur. Indeed, mem bers of the steroid hormone receptor family as well as RA receptors achieve transcriptional control by inductive as well as inhibitory mechanisms. It is logical, therefore, that the effects of RA and its receptors on genes coding for hormones and growth factors should have been the sub ject of considerable investigation in the past few years. RARs activated by related ligands regulate the tran scription of specific genes by binding to identifiable response elements occurring in the promoter regions of these genes. A high degree of homology has been found between RAREs and the T3 receptor binding DNA do main (the TRE, thyroid hormone responsive element). In fact, genes which contain the TRE can be transactivated by RARs [11], In the pituitary cell line GH1, T 3 stimu lates growth hormone production. These cells also re spond to RA, which stimulates growth hormone produc tion on its own as well as synergistically with T 3 and dexamethasone. The RA-receptor complexes are thought to interact with DNA sequences to alter the expression of the growth hormone gene [29]. The polypeptide growth factors, such as the epidermal growth factor (EGF) and transforming growth fractor alpha (TGF-a), stimulate growth, whereas TGF-p can either stimulate or inhibit growth depending upon the tar get cell type. The interaction of RA in growth control by these growth factors has provided much information per taining to the control of cellular proliferation and growth in normal and neoplastic systems. Growth promoters such as EGF, the phorbol ester tumour promoter TPA and second messengers such as cyclic AMP are positive transcriptional regulators of the EGF receptor promoter [30], The promoter of the erhB2/neu gene, which codes for a tyrosine kinase growth factor receptor, is also positively regulated by these agents [31], although a specific ligand for this receptor is yet to be discovered. On the other hand, activated T 3and RA receptors both inhibit the EGF receptor and the erbB2 gene [32], In HL-60 promyelocytic leukaemia cells, RA inhibits proliferation in a dose-dependent fashion and induces granulocytic differentiation. According to Falk et al. [33] this appears to be the result of an enhanced expression of TGF-Pi receptors on the cell surface, together with an
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the homeobox of hox 1.5 mouse show sequence specific DNA binding in vitro [15, 16], which suggests that ho meobox containing proteins may regulate specific sets of genes. It has been suggested, therefore, that the in vivo and in vitro effects of RA might involve homeobox con taining genes, of which ERA-1 is a prime example. Other authors have described the activation of hox genes related to exposure of embryonal carcinoma cells in culture to RA. but not related to the process of differentiation [17, 18]. Stornaiuolo et al. [19] studied the expression of 33 human homeobox (hox) genes belonging to four hox loci in the embryonal carcinoma NT2/D1 cells. Whereas none of these genes were normally expressed in N T2/D 1 cells, 22 were induced to express upon treatment with RA. The 1 1 hox genes which could not be induced were located in the 5' region of the hox"loci. Furthermore, both this study by Stornaiuolo et al. [ 19] and the previous one by Breier et al. [20] have indicated that the homeobox genes are differ entially expressed in response to RA. The expression of these genes could conceivably determine the activation of regionally important genes, such as those involved in pat tern formation. Chisaka and Capecchi [21] have demon strated quite convincingly that hox genes also regulate vertebrate development and that spatial and temporal dif ferentiation may be determined by the ‘positional infor mation’ flowing from the different combinations of hox gene expression.
Regulation of Genes Coding for Proteinases One of the important properties of TNF is its ability to degrade the extracellular matrix. Collagenase and stromelysin are two prominent metalloproteinases taking part in the degradation of the extracellular matrix [41,42]. It has been reported that TNF-a increases collagenase produc tion by human synovial cells and skin Fibroblasts [43]. Chua and Chua [44] found that the cytokine induced a 10-fold increase in collagenase gene transcripts following treatment of skin fibroblasts by TNF. It also induced the activity of tissue inhibitor of metalloproteinases (TIMP). Ito et al. [45] have also reported that collagenase and stromelysin are induced by TNF in a dose-dependent fashion. TIMP is induced by TNF at low concentrations but the increased synthesis of TIMP is inhibited at high concentration ranges of TNF. The induction of both the enzyme and the inhibitor has been reported in the case of other growth factors such as interleukin I (IL-1) and growth promoters like TPA [46], It may be that there is regulation of the expression of collagenase and TIMP which is dependent upon the endogenous levels of TNF, which in its turn may be controlled by RA. Strickland and Mahdavi [47] observed that F9 embryonal carcinoma cell differentiation following exposure to RA was accompa nied by increased synthesis and secretion of plasminogen activator. Wang and Gudas [48] have shown that one of
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the cDNA clones expressed abundantly in these cells after RA exposure codes for a proteinase inhibitor belonging to the serine proteinase inhibitor family. Thus a co-ordi nated regulation of expression of both proteinases and their inhibitors might not be an uncommon phenome non. The regulation of the genes coding for collagenase and stromelysin has been studied recently. Lafyatis et al. [49] showed that IL-1 enhances collagenase secretion by in creasing the steady state levels of the collagenase gene transcripts. RA has the opposite effect. Both the negative and positive regulatory effects have been found to be mediated by the TPA-responsive elements. The transcrip tion factor AP-1 binds to the TPA-responsive element and increases transcription. The AP-1 itself is a hetero dimer complex consisting of fos and jun proteins. Both IL-1 and TPA (which is itself capable of inducing the col lagenase gene) induce these early response genes. How ever, RA down-regulates only the fos but not th ajun onco gene, suggesting that RA might inhibit transcription of the collagenase gene by inhibiting fos expression. Expression of the stromelysin gene is also inhibited by RA and this effect is mediated by a 25 Kb 5'-flanking DNA sequence of the stromelysin gene which includes the AP-1 binding site [50].
Modulation of Metastasis-Associated Genes Retinoic acid has been shown consistently to inhibit the process of cancer invasion and metastasis [51-54], The inhibition of cellular invasion is accompanied by a decreased expression of proteolytic enzymes such as collagenases and plasminogen activator which enable the deg radation of the extracellular matrix components [51, 52], RA has also been known to induce the synthesis of extra cellular matrix proteins such as laminin and collagen IV and higher steady state levels of mRNA coding for these proteins are evident in cells following RA treatment [55], These alterations can affect the adhesive abilities of tumour cells and as a consequence alter the metastatic behaviour of tumour cells [56], Several genes are known to be differentially expressed in normal cells and their malignant counterparts. Among these are genes coding for fibronectin [57] and the WDNM1 and WDNM2 genes [58, 59], These genes are expressed at a reduced level, while the proteinase transin (stromelysin) gene is expressed more abundantly in malig nant tumours [60], A metastasis suppressor gene, the nm23. has been described in murine melanomas [61,62],
Modulation of Gene Function by Retinoic Acid
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enhanced expression of TGF-(3i gene. TGF-P and RA act synergistically to inhibit phorbol ester induced cellular transformation. This is due in part to modulation of the TGF-P receptor expression [34], In cultured kératino cytes, the inhibition of DNA synthesis by RA is accompa nied by an increased expression of TGF-P2. The latter is secreted in the active form and can then bind to surface receptors [35]. Glick et al. have also shown that anti-TGFP2 antibodies abrogate the ability of RA to inhibit DNA synthesis. Tumour necrosis factor (TNF) is a cytokine released by macrophages and monocytic cells stimulated by lipopoly saccharide [36], TNF is highly cytotoxic, causes necrosis of solid tumours [36, 37] and inhibits the growth of both normal and tumour cells in vitro [38, 39], The release of TNF by LPS stimulation of peripheral blood monocytes has been found to require the presence of endogenous RA. However, neither the intracellular levels of TNF nor TNF mRNA were affected by the removal of RA [40]. This sug gests that RA may not be directly involved with the posi tive regulation of the TNF gene.
A dominant metastasis gene, mlsl, has been reported which is highly expressed in high metastasis murine tumours and human tumours grown as xenografts [63, 64], Thus there are a number of candidate metastasis genes, i.e. those postulated to be the determinants of the metastatic behaviour, as well as target genes, such as the laminin, collagenase, and stromelysin genes, which might control specific events in the metastatic cascade. There is a considerable body of evidence which sup ports the association between the putative candidate me tastasis genes such as the mtsl and the nm23 but it ought to be emphasised that the evidence is mainly empirical. Recently Parker et al. [54] have modulated the metastatic behaviour of the B16 murine melanoma variants using RA and have examined whether the expression of these genes is also concomitantly modulated. They have re ported that RA decreased lung colonisation by the high metastasis variant BL6 and MLS melanomas and in par allel down-regulated the mtsl gene. The expression of mn23 did not show an inverse relationship to the meta static potential of the melanoma variants. Nevertheless, RA upregulated its expression, albeit not in a consistent fashion. Parker et al. [54] also found that melanocyte stimulating hormone (MSH) increased lung colonisation by the low metastasis variant B16-F1, with a parallel increase in m lsl expression. MSH did not alter the expression of the nm23 gene. The patterns of changes of expression were not always consistent with RA treatment, but the pattern of changes in the ratios of nm23 and mlsl expression has suggested that these two genes are co-ordi nately regulated by RA. There were substantial differ ences between the variant cell lines in their transcrip tional regulation of the genes, i.e. both genes appear to be transcriptionally less responsive in the low malignancy variant than in the high metastasis variant. In addition, it appeared that the nm23 gene is transcriptionally more responsive than the mlsl in the high metastasis variant.
The effects of these two genes on the expression of the phenotypic behaviour of tumour cells may be comple mentary and, whereas in low metastasis variants their reg ulation may be closely interlinked, in high metastasis variants there could be an uncoupling of the mechanisms of regulation. We are currently elucidating the signal transduction pathways by which MSH and RA regulate the expression of mlsl and nm23 genes and how these pathways are interlinked. MSH is known to stimulate adenylate cyclase (AC) activity and increase the intracellular levels of cAMP. This in turn will activate the protein kinase A (PKA) signal transduction pathway. A consequence of this is a transient increase in the expression of the early response genes c-fos and junB [Parker et al., unpubl. observations] which code tor the transcription activating protein heterodimer API. Increased mtsl expression in the low metastasis variant B16F1 after treatment with MSH may be via activation of these genes. The 3' region of the gene contains an API-like sequence which is homologous to an API enhancer element in the 3' region of the chick (i-globin gene. Retinoic acid, on the other hand, has been shown to lower the basal levels and MSH stimulated AC activity [65] and the down-regulation of mtsl expression in the high metastasis variant BL6 and ML8 melanomas by RA may be due to a reduction in AC activity and subsequent PKA mediated signal transduction.
Acknowledgments This work was supported by grants from the North of England Cancer Research Campaign and the Tom Berry Memorial Fund.
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