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• W2041229746 abstract "Multiple cellular effects of human growth hormone (hGH) are mediated by an indirect mechanism requiring transcriptional activation of genes encoding protein effector molecules such as insulin-like growth factor-1. Such protein effector molecules then act directly to mediate the cellular functions of hGH. We report here that autocrine hGH production by mammary carcinoma cells specifically results in the transcriptional repression of the p53-regulated placental transforming growth factor-β (PTGF-β) gene. Transcriptional repression of the PTGF-β gene does not require the p53-binding sites in the PTGF-β promoter, and autocrine hGH also desensitized the response of thePTGF-β promoter to p53 overexpression. Transcriptional repression of the PTGF-β gene is accompanied by consequent decreases in its protein product, Smad-mediated transcription, and its cellular effects that include cell cycle arrest and apoptosis. PTGF-β specifically inhibited the autocrine hGH-stimulated expression of cyclin D1 required for autocrine hGH-stimulated mammary carcinoma cell cycle progression. Thus, one mechanism by which autocrine hGH promotes an increase in mammary carcinoma cell number is by transcriptional repression of protein effector molecules that promote cell cycle arrest and apoptosis. Such transcriptional repression of negative regulatory factors, such as PTGF-β, may also be requisite for direct stimulation of mammary carcinoma cell mitogenesis by hGH. Multiple cellular effects of human growth hormone (hGH) are mediated by an indirect mechanism requiring transcriptional activation of genes encoding protein effector molecules such as insulin-like growth factor-1. Such protein effector molecules then act directly to mediate the cellular functions of hGH. We report here that autocrine hGH production by mammary carcinoma cells specifically results in the transcriptional repression of the p53-regulated placental transforming growth factor-β (PTGF-β) gene. Transcriptional repression of the PTGF-β gene does not require the p53-binding sites in the PTGF-β promoter, and autocrine hGH also desensitized the response of thePTGF-β promoter to p53 overexpression. Transcriptional repression of the PTGF-β gene is accompanied by consequent decreases in its protein product, Smad-mediated transcription, and its cellular effects that include cell cycle arrest and apoptosis. PTGF-β specifically inhibited the autocrine hGH-stimulated expression of cyclin D1 required for autocrine hGH-stimulated mammary carcinoma cell cycle progression. Thus, one mechanism by which autocrine hGH promotes an increase in mammary carcinoma cell number is by transcriptional repression of protein effector molecules that promote cell cycle arrest and apoptosis. Such transcriptional repression of negative regulatory factors, such as PTGF-β, may also be requisite for direct stimulation of mammary carcinoma cell mitogenesis by hGH. human growth hormone placental transforming growth factor-β fetal bovine serum 5′-bromo-2′-deoxyuridine transforming growth factor-β poly(ADP-ribose) polymerase Smad-binding element analysis of variance reverse transcriptase 17-β-estradiol insulin-like growth factor human IGF growth hormone mitogen-activated protein phosphate-buffered saline The human growth hormone (hGH)1 gene is expressed in epithelial cells of the normal human mammary gland. 2M. Raccurt, P. E. Lobie, E. Moudilou, S. Recher, T. Garcia-Caballero, L. Frappart, G. Morel, and H. C. Mertani, submitted for publication.2M. Raccurt, P. E. Lobie, E. Moudilou, S. Recher, T. Garcia-Caballero, L. Frappart, G. Morel, and H. C. Mertani, submitted for publication. Increased epithelial expression of the hGH gene is associated with the acquisition of pathological proliferation, and the highest level of hGH gene expression is observed in metastatic mammary carcinoma cells.2 hGH receptor gene expression per mammary epithelial cell remains constant throughout the process of neoplastic progression (1Mertani H.C. Garcia-Caballero T. Lambert A. Gerard F. Palayer C. Boutin J.M. Vonderhaar B.K. Waters M.J. Lobie P.E. Morel G. Int. J. Cancer. 1998; 79: 202-211Crossref PubMed Scopus (137) Google Scholar), and therefore changes in the local concentration of ligand are likely to be pivotal to determine the effects of hGH on the behavior of the mammary epithelial cell. We have recently generated a model system to study the role of autocrine-produced hGH in mammary carcinoma by stable transfection of either the hGH gene or a translation-deficient hGH gene into mammary carcinoma (MCF-7) cells (2Kaulsay K.K. Mertani H.C. Tornell J. Morel G. Lee K.O. Lobie P.E. Exp. Cell Res. 1999; 250: 35-50Crossref PubMed Scopus (102) Google Scholar). The autocrine production of hGH by mammary carcinoma cells results in a hyperproliferative state with marked synergism observed between trophic agents such as IGF-1 (2Kaulsay K.K. Mertani H.C. Tornell J. Morel G. Lee K.O. Lobie P.E. Exp. Cell Res. 1999; 250: 35-50Crossref PubMed Scopus (102) Google Scholar). The increase in mammary carcinoma cell number as a consequence of autocrine production of hGH is a result of both increased mitogenesis and decreased apoptosis (3Kaulsay K.K. Zhu T. Bennett W. Lee K.O. Lobie P.E. Endocrinology. 2001; 142: 767-777Crossref PubMed Scopus (81) Google Scholar). Autocrine hGH production also results in enhancement of the rate of mammary carcinoma cell spreading on a collagen substrate (4Kaulsay K.K. Mertani H.C. Lee K.O. Lobie P.E. Endocrinology. 2000; 141: 1571-1584Crossref PubMed Scopus (30) Google Scholar), suggesting that it may affect cell motility and dissemination of the carcinoma. All of the studied effects of autocrine hGH on mammary carcinoma cell behavior are mediated via the hGH receptor (3Kaulsay K.K. Zhu T. Bennett W. Lee K.O. Lobie P.E. Endocrinology. 2001; 142: 767-777Crossref PubMed Scopus (81) Google Scholar). Thus, autocrine production of hGH by mammary carcinoma cells may direct mammary carcinoma cell behavior to impact on the final clinical prognosis. Systematic analysis of the relevant mechanistic features by which autocrine hGH exerts its cellular effects is therefore required.One major mechanism by which GH affects cellular and somatic function is by regulating the level of specific mRNA species (5Isaksson O.G. Eden S. Jansson J.O. Annu. Rev. Physiol. 1985; 47: 483-499Crossref PubMed Google Scholar). Some of these GH-regulated genes code for trophic factors such as IGF-1 (6Klapper D.G. Svoboda M.E. Van Wyk J.J. Endocrinology. 1983; 112: 2215-2217Crossref PubMed Scopus (224) Google Scholar), which act in an intermediary role to execute the cellular effects of GH. Indeed, GH has been demonstrated to regulate the level of a number of trophic factors in specific tissues including hepatocyte growth factor in liver (7Ekberg S. Luther M. Nakamura T. Jansson J.O. J. Endocrinol. 1992; 135: 59-67Crossref PubMed Scopus (52) Google Scholar), epidermal growth factor in kidney (8Rogers S.A. Rasmussen J. Miller S.B. Hammerman M.R. Am. J. Physiol. 1994; 267: F208-F214PubMed Google Scholar), basic fibroblast growth factor in chondrocytes (9Izumi T. Shida J. Jingushi S. Hotokebuchi T. Sugioka Y. Mol. Cell. Endocrinol. 1995; 112: 95-99Crossref PubMed Scopus (21) Google Scholar), interleukin-6 in osteoblasts (10Swolin D. Ohlsson C. J. Clin. Endocrinol. Metab. 1996; 81: 4329-4333Crossref PubMed Scopus (30) Google Scholar), bone morphogenetic proteins 2 and 4 in fibroblasts (11Li H. Bartold P.M. Zhang C.Z. Clarkson R.W. Young W.G. Waters M.J. Endocrinology. 1998; 139: 3855-3862Crossref PubMed Scopus (55) Google Scholar), interleukin-1α and interleukin-1β in thymus (12Tseng Y.H. Kessler M.A. Schuler L.A. Mol. Cell. Endocrinol. 1997; 128: 117-127Crossref PubMed Scopus (34) Google Scholar), and preadipocyte factor-1 in adipocytes (13Hansen L.H. Madsen B. Teisner B. Nielsen J.H. Billestrup N. Mol. Endocrinol. 1998; 12: 1140-1149Crossref PubMed Google Scholar) and islet β-cells (14Carlsson C. Tornehave D. Lindberg K. Galante P. Billestrup N. Michelsen B. Larsson L.I. Nielsen J.H. Endocrinology. 1997; 138: 3940-3948Crossref PubMed Scopus (83) Google Scholar). It is therefore likely that many of the effects of autocrine hGH on mammary carcinoma cell function are also mediated by genetic regulation of specific trophic factors. Here we have used a cDNA microarray to identify autocrine hGH-regulated genes encoding polypeptide effector molecules that will act in an intermediary manner to mediate the effects of hGH on mammary carcinoma cell function.We observed that autocrine hGH decreased transcription of thePTGF-β gene with consequent decreases in its protein product and accompanying cellular effects, which include cell cycle arrest and apoptosis. PTGF-β specifically inhibited the autocrine hGH-stimulated expression of cyclin D1 to prevent mammary carcinoma cell cycle progression. Thus, one mechanism by which autocrine hGH promotes mammary carcinoma cell survival is by transcriptional repression of protein effector molecules that promote cell cycle arrest and apoptosis. Such a mechanism is analogous and complementary to the ability of hGH to transcriptionally activate protein effector molecules, such as IGF-1, which stimulate processes resulting in increased cell number (15Le Roith D. Bondy C. Yakar S. Liu J.L. Butler A. Endocr. Rev. 2001; 22: 53-74Crossref PubMed Scopus (859) Google Scholar).DISCUSSIONWe have demonstrated here that autocrine production of hGH by mammary carcinoma cells results in a specific decrease ofPTGF-β gene transcription. Thus, autocrine hGH function in the mammary epithelial cell, such as mitogenesis and cell survival, may be partly mediated by, or first require, repression of the inhibitory effects of PTGF-β. Furthermore, because PTGF-β is a secreted protein, it will also act in a paracrine fashion to affect the function of neighboring cells. In carcinoma of the mammary gland, such paracrine interactions usually occur between carcinoma cells of epithelial origin and neighboring stromal fibroblasts and are pivotal to the development of carcinoma (36Elenbaas B. Weinberg R.A. Exp. Cell Res. 2001; 264: 169-184Crossref PubMed Scopus (443) Google Scholar). It is noteworthy to mention that the hGH receptor is predominantly expressed on the normal or neoplastic epithelial cells of the human mammary gland, and therefore autocrine hGH production by mammary epithelial cells will, via the paracrine action of PTGF-β, affect stromal cell function. For example, fibroadenoma of the mammary gland, where we observe increased expression of the hGH gene in epithelial cells,2 exhibits an intense stromal reaction. It is possible that loss of paracrine PTGF-β secretion by the mammary epithelial cell in response to autocrine hGH production may contribute to changes in stromal architecture. TGF-β secreted by mammary carcinoma cells has been demonstrated to affect stromal architecture and tumor progression (36Elenbaas B. Weinberg R.A. Exp. Cell Res. 2001; 264: 169-184Crossref PubMed Scopus (443) Google Scholar). Use of in vivo models will allow us to define the effect of autocrine production of hGH by mammary epithelial or mammary carcinoma cells on the surrounding stroma and delineate the relative contribution to neoplastic progression.PTGF-β is a recently identified secretory protein that shares ∼25% sequence identity with TGF-β family members (23Lawton L.N. Bonaldo M.F. Jelenc P.C. Qiu L. Baumes S.A. Marcelino R.A. de Jesus G.M. Wellington S. Knowles J.A. Warburton D. Brown S. Soares M.B. Gene (Amst.). 1997; 203: 17-26Crossref PubMed Scopus (148) Google Scholar) and possesses several characteristics of the TGF-β superfamily including a signal peptide, a consensus RXXR(A/S) cleavage signal for processing to the mature form, and seven conserved cysteine residues in the carboxyl terminus (mature form) (22Bootcov M.R. Bauskin A.R. Valenzuela S.M. Moore A.G. Bansal M., He, X.Y. Zhang H.P. Donnellan M. Mahler S. Pryor K. Walsh B.J. Nicholson R.C. Fairlie W.D. Por S.B. Robbins J.M. Breit S.N. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 11514-11519Crossref PubMed Scopus (851) Google Scholar, 23Lawton L.N. Bonaldo M.F. Jelenc P.C. Qiu L. Baumes S.A. Marcelino R.A. de Jesus G.M. Wellington S. Knowles J.A. Warburton D. Brown S. Soares M.B. Gene (Amst.). 1997; 203: 17-26Crossref PubMed Scopus (148) Google Scholar, 37Yokoyama-Kobayashi M. Saeki M. Sekine S. Kato S. J. Biochem. (Tokyo). 1997; 122: 622-626Crossref PubMed Scopus (94) Google Scholar, 38Hromas R. Hufford M. Sutton J., Xu, D., Li, Y. Lu L. Biochim. Biophys. Acta. 1997; 1354: 40-44Crossref PubMed Scopus (191) Google Scholar, 39Paralkar V.M. Vail A.L. Grasser W.A. Brown T.A., Xu, H. Vukicevic S., Ke, H.Z., Qi, H. Owen T.A. Thompson D.D. J. Biol. Chem. 1998; 273: 13760-13767Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). PTGF-β has also been demonstrated to utilize either the type I TGF-β receptor or type II TGF-β receptor to mediate cell cycle arrest (16Tan M. Wang Y. Guan K. Sun Y. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 109-114Crossref PubMed Scopus (227) Google Scholar). Activation of type I TGF-β receptor or type II TGF-β receptor results in a complex series of downstream signaling events resulting in phosphorylation of Smad proteins that translocate to the nucleus, associate with transcriptional co-activators, and transactivate TGF-β-regulated genes (40Liu X.P. Tsushimi K. Tsushimi M. Kawauchi S. Oga A. Furuya T. Sasaki K. Cancer Lett. 2001; 170: 183-189Crossref PubMed Scopus (36) Google Scholar). We also observed here that autocrine production of hGH by mammary carcinoma cells results in decreased Smad-mediated gene transcription in accord with the decreased production of PTGF-β. Other mechanisms may also exist for the observed autocrine hGH-stimulated decrease in Smad-mediated transcription. By use of cDNA microarray technology we have reported recently (24Mertani H.C. Zhu T. Goh E.L. Lee K.O. Morel G. Lobie P.E. J. Biol. Chem. 2001; 276: 21464-21475Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar) that the ski oncogene is ∼4-fold up-regulated in response to autocrine production of hGH. It has been demonstrated recently that ski associates with both Smad2 and Smad3 resulting in repression of TGF-β-responsive promoters via the Smad-binding element (SBE) used here (41Fawcett T.W., Xu, Q. Holbrook N.J. Cell Stress Chaperones. 1997; 2: 104-109Crossref PubMed Scopus (49) Google Scholar). The TGF-β pathway usually functions to suppress cellular proliferation and cellular transformation. It has been proposed that the repression of TGF-β-inducible genes (which function as negative regulators of cell cycle function in mammary epithelial cells) may be pivotal to the cellular transforming ability of ski (41Fawcett T.W., Xu, Q. Holbrook N.J. Cell Stress Chaperones. 1997; 2: 104-109Crossref PubMed Scopus (49) Google Scholar). Thus, autocrine hGH production by mammary carcinoma cells acts in concert to both induce negative regulators and suppress positive regulators of the TGF-β pathway. That autocrine production of hGH by mammary carcinoma cells results in such coordinated repression of the TGF-β axis is suggestive that many functions of autocrine hGH in mammary epithelial cells may be achieved by simple antagonism of this pathway.PTGF-β was identified as a p53-regulated gene (16Tan M. Wang Y. Guan K. Sun Y. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 109-114Crossref PubMed Scopus (227) Google Scholar, 25Li P.X. Wong J. Ayed A. Ngo D. Brade A.M. Arrowsmith C. Austin R.C. Klamut H.J. J. Biol. Chem. 2000; 275: 20127-20135Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). We have demonstrated here that autocrine production of hGH by mammary carcinoma cells decreased transcription of the PTGF-β gene in a p53-independent manner. Thus, we observe that autocrine production of hGH results in a similar percentage decrease in PTGF-βgene transcription in the absence of the two putative p53-binding sites in the PTGF-β promoter, and the inhibitory effect of autocrine production of hGH by MCF-hGH cells on the PTGF-β promoter was maintained when several PTGF-β gene promoter inactive (p53-(1–143) and p53-(1–273)) or active (p53-(1–281)) mutants of p53 (16Tan M. Wang Y. Guan K. Sun Y. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 109-114Crossref PubMed Scopus (227) Google Scholar, 42Hollstein M. Sidransky D. Vogelstein B. Harris C.C. Science. 1991; 253: 49-53Crossref PubMed Scopus (7411) Google Scholar) were utilized. Thus autocrine production of hGH by mammary epithelial cells will antagonize the cellular response to p53 and therefore promote inappropriate cell survival potentially leading to neoplastic transformation. p53 is an important mediator of the cellular response to DNA damage and activates genes responsible for both cell cycle arrest and apoptosis (43Gewirtz D.A. Breast Cancer Res. Treat. 2000; 62: 223-235Crossref PubMed Scopus (65) Google Scholar). However, inhibition of p53-regulated genes by autocrine production of hGH is not a general cellular response as autocrine hGH has been demonstrated previously by us to up-regulate two p53 regulated genes, namely GADD45(24Mertani H.C. Zhu T. Goh E.L. Lee K.O. Morel G. Lobie P.E. J. Biol. Chem. 2001; 276: 21464-21475Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar) and p21 waf1/cip1 . 3R. Graichen and P. E. Lobie, unpublished observations.Furthermore, IGF-BP3 is both a p53- (44Buckbinder L. Talbott R. Velasco-Miguel S. Takenaka I. Faha B. Seizinger B.R. Kley N. Nature. 1995; 377: 646-649Crossref PubMed Scopus (804) Google Scholar) and hGH-regulated (45Kato Y., Hu, H.Y. Sohmiya M. Endocr. J. 1996; 43: 177-183Crossref PubMed Scopus (6) Google Scholar) gene. Interestingly, there exists a STAT-binding site in the promoter region of the PTGF-β gene (25Li P.X. Wong J. Ayed A. Ngo D. Brade A.M. Arrowsmith C. Austin R.C. Klamut H.J. J. Biol. Chem. 2000; 275: 20127-20135Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar), and this may constitute one mechanism for the observed effect of autocrine hGH onPTGF-β gene transcription. STAT molecules can either stimulate or repress transcription depending on the promoter context (46Luo G. Yu-Lee L. J. Biol. Chem. 1997; 272: 26841-26849Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 47Groner B. Fritsche M. Stocklin E. Berchtold S. Merkle C. Moriggl R. Pfitzner E. Growth Horm. IGF Res. 2000; 10 (suppl.): 15-20Crossref Scopus (29) Google Scholar), and hGH has been demonstrated to utilize STATs for many of its transcriptional effects (48Zhu T. Goh E.L. Graichen R. Ling L. Lobie P.E. Cell. Signal. 2001; 13: 599-616Crossref PubMed Scopus (220) Google Scholar). Further analysis of the PTGF-β promoter should allow for the precise definition of the regulatory elements utilized by autocrine hGH to suppress PTGF-β gene transcription.We have reported previously that autocrine production of hGH by mammary carcinoma cells results in increased entry to S-phase (3Kaulsay K.K. Zhu T. Bennett W. Lee K.O. Lobie P.E. Endocrinology. 2001; 142: 767-777Crossref PubMed Scopus (81) Google Scholar) and increased cell number (2Kaulsay K.K. Mertani H.C. Tornell J. Morel G. Lee K.O. Lobie P.E. Exp. Cell Res. 1999; 250: 35-50Crossref PubMed Scopus (102) Google Scholar). We observe here that forced expression of PTGF-β completely prevents S-phase entry by either MCF-MUT or MCF-hGH cells. Thus, decreased expression of PTGF-β would be required for autocrine hGH to promote cell cycle progression of mammary epithelial cells. However, exogenous application of hGH to mammary carcinoma cells (MCF-7) still results in equivalent entry to S-phase (3Kaulsay K.K. Zhu T. Bennett W. Lee K.O. Lobie P.E. Endocrinology. 2001; 142: 767-777Crossref PubMed Scopus (81) Google Scholar) but without a decrease in PTGF-β expression (this study). It may be that high expression of PTGF-β is incompatible with neoplastic proliferation, and therefore MCF-7 cells already have diminished PTGF-β expression below a critical threshold required for survival and cell cycle progression. This would therefore allow proliferation in response to a mitogen such as exogenously applied hGH without further decreases in the level of PTGF-β. This is concordant with the fact that forced expression of PTGF-β alone results in cell cycle arrest and apoptosis of mammary carcinoma cells (this study and Ref. 25Li P.X. Wong J. Ayed A. Ngo D. Brade A.M. Arrowsmith C. Austin R.C. Klamut H.J. J. Biol. Chem. 2000; 275: 20127-20135Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar), including mammary carcinoma cells with autocrine production of hGH. It is interesting to note that autocrine hGH production by mammary carcinoma cells results in dramatically increased p21Waf1/Cip1 expression. Increased p21Waf1/Cip1 expression has been associated previously with inhibition of cell cycle progression stimulated by either PTGF-β (16Tan M. Wang Y. Guan K. Sun Y. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 109-114Crossref PubMed Scopus (227) Google Scholar) or TGF-β (49Salatino M. Labriola L. Schillaci R. Charreau E.H. Elizalde P.V. Exp. Cell Res. 2001; 265: 152-166Crossref PubMed Scopus (10) Google Scholar), and we also observe here that forced expression of PTGF-β in MCF-MUT cells results in increased p21Waf1/Cip1. This observation is concordant with the published role of p21Waf1/Cip1 as the major mediator of p53 induced G1 arrest (50el-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7889) Google Scholar). However, other investigators (51Jeay S. Sonenshein G.E. Kelly P.A. Postel-Vinay M.C. Baixeras E. Endocrinology. 2001; 142: 147-156Crossref PubMed Scopus (53) Google Scholar) have also demonstrated recently that autocrine GH results in specific up-regulation of p21Waf1/Cip1 in Ba/F3 cells associated with cell proliferation. We also report here decreased p27Kip1 expression in MCF-hGH compared with MCF-MUT cells. Interestingly, Raf-mediated cell proliferation is associated with elevated p21Waf1/Cip1, which specifically binds to and activates Cdk4-cyclin D complexes and also with decreased p27Kip1 expression (52Chang F. McCubrey J.A. Oncogene. 2001; 20: 4354-4364Crossref PubMed Scopus (39) Google Scholar). Autocrine hGH production by mammary carcinoma cells results in increased raf gene expression (24Mertani H.C. Zhu T. Goh E.L. Lee K.O. Morel G. Lobie P.E. J. Biol. Chem. 2001; 276: 21464-21475Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar), and this may be the mechanism for the observed changes in p21Waf1/Cip1 and p27Kip1 expression. In any case, cell cycle arrest as a consequence of forced expression of PTGF-β in MCF-hGH cells is not due to increased expression of p21Waf1/Cip1. We did observe that autocrine hGH stimulation of mammary carcinoma cells resulted in a dramatic increase in the level of cyclin D1 concordant with the observed increased entry of MCF-hGH cells to S-phase compared with MCF-MUT cells. The level of cyclin D1 is elevated in a high percentage of carcinomas of the mammary gland (53Barnes D.M. J. Pathol. 1997; 181: 267-269Crossref PubMed Scopus (52) Google Scholar), and cyclin D1 overexpression in transgenic mice results in formation of mammary carcinoma (54Wang T.C. Cardiff R.D. Zukerberg L. Lees E. Arnold A. Schmidt E.V. Nature. 1994; 369: 669-671Crossref PubMed Scopus (890) Google Scholar). Increased expression of cyclin D1 has also been demonstrated to be sufficient for G1 progression in mammary carcinoma cells (28Musgrove E.A. Hui R. Sweeney K.J. Watts C.K. Sutherland R.L. J. Mamm. Gland. Biol. Neoplasia. 1996; 1: 153-162Crossref PubMed Scopus (36) Google Scholar). Forced expression of PTGF-β prevented the autocrine hGH-stimulated increase in cyclin D1 observed in MCF-hGH cells. The mechanism by which PTGF-β prevents the autocrine hGH-stimulated increase in cyclin D1 remains to be determined. The level of cyclin D1 is predominantly regulated at the transcriptional level by rapid changes in the activity of the cyclin D1 promoter which is under complex control by multiple signaling pathways (55Pestell R.G. Albanese C. Reutens A.T. Segall J.E. Lee R.J. Arnold A. Endocr. Rev. 1999; 20: 501-534Crossref PubMed Scopus (317) Google Scholar). We observed here that autocrine hGH production in mammary carcinoma cells results in increased transcription of the cyclin D1 gene which is specifically repressed by PTGF-β. Although p44/42 MAP kinase has been demonstrated to be required for cyclin D1 gene expression (56Amanatullah D.F. Zafonte B.T. Albanese C., Fu, M. Messiers C. Hassell J. Pestell R.G. Methods Enzymol. 2001; 333: 116-127Crossref PubMed Scopus (19) Google Scholar), we have observed that both autocrine hGH and PTGF-β resulted in increased activation of p44/42 MAP kinase in mammary carcinoma cells, 4D.-X. Liu, R. Graichen, and P. E. Lobie, unpublished observations. and therefore PTGF-β inhibition of cyclin D1 expression is not p44/42 MAP kinase-dependent. The transcription of the cyclin D1 gene is also regulated by STAT5 (57Matsumura I. Kitamura T. Wakao H. Tanaka H. Hashimoto K. Albanese C. Downward J. Pestell R.G. Kanakura Y. EMBO J. 1999; 18: 1367-1377Crossref PubMed Scopus (290) Google Scholar), and STAT5 is required for GH-stimulated mitogenesis of islet β-cells (58Friedrichsen B.N. Galsgaard E.D. Nielsen J.H. Moldrup A. Mol. Endocrinol. 2001; 15: 136-148Crossref PubMed Scopus (63) Google Scholar). We have observed that PTGF-β decreases STAT5-mediated transcription in mammary carcinoma cells,3 and whether this constitutes the mechanism of the observed PTGF-β decrease in cyclin D1 is under investigation. In any case PTGF-β prevents autocrine hGH-stimulated mammary carcinoma cell cycle progression by inhibition of autocrine hGH-stimulated cyclin D1 expression.In addition to blocking cell cycle progression of mammary carcinoma cells in response to autocrine production of hGH, we observed that forced expression of PTGF-β resulted in apoptotic cell death. Overexpression of PTGF-β has also been demonstrated by other investigators to result in apoptotic cell death of mammary carcinoma cells (25Li P.X. Wong J. Ayed A. Ngo D. Brade A.M. Arrowsmith C. Austin R.C. Klamut H.J. J. Biol. Chem. 2000; 275: 20127-20135Abstract Full Text Full Text PDF PubMed Scopus (232) Google Scholar). In this regard it is interesting that the decreased transcription of the PTGF-β gene is only observed with autocrine-produced and not exogenously added hGH. Similarly, protection from apoptotic cell death is also only provided by autocrine-produced and not exogenously added hGH (3Kaulsay K.K. Zhu T. Bennett W. Lee K.O. Lobie P.E. Endocrinology. 2001; 142: 767-777Crossref PubMed Scopus (81) Google Scholar). Thus the suppression of PTGF-β gene transcription by autocrine hGH may be one mechanism by which autocrine hGH differentially affects mammary carcinoma cell behavior in contrast to exogenously added or “endocrine” hGH. Presumably the decreased production of PTGF-β will also result in the diminished transcription of pro-apoptotic genes and release of transcriptional repression of genes required for cell survival. Cell survival and cell death genes regulated by PTGF-β in mammary carcinoma cells remain to be identified. hGH may also directly regulate genes required for cell survival, and we have demonstrated recently that autocrine hGH increases transcription of theCHOP gene to result in survival of mammary carcinoma cells in a p38 MAP kinase-dependent manner (24Mertani H.C. Zhu T. Goh E.L. Lee K.O. Morel G. Lobie P.E. J. Biol. Chem. 2001; 276: 21464-21475Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). What needs to be determined is the mechanism and sequential order by which these genes are regulated by autocrine production of hGH. Detailed and sequential promoter analyses, identification of the relevant transcription factor response elements combined with the relevant dissection of upstream signaling pathways, should allow for the identification of primaryversus secondary or tertiary events in the effects of autocrine hGH on mammary carcinoma cell behavior and in particular apoptotic cell death.In conclusion, we have demonstrated that autocrine production of hGH by mammary carcinoma cells results in transcriptional repression of thePTGF-β gene with consequent decreases in its protein product and accompanying cellular effects that include cell cycle arrest and apoptosis. Thus, one mechanism by which autocrine hGH promotes mammary carcinoma cell survival is by transcriptional repression of protein effector molecules that promote cell cycle arrest and apoptosis. Such a mechanism is analogous and complementary to the ability of hGH to activate transcriptionally the protein effector molecules that stimulate cell cycle progression and cell survival (15Le Roith D. Bondy C. Yakar S. Liu J.L. Butler A. Endocr. Rev. 2001; 22: 53-74Crossref PubMed Scopus (859) Google Scholar). It remains to be determined what effects of autocrine hGH on mammary carcinoma cell behavior are mediated directly by autocrine hGH or indirectly via utilization of effector molecules, which themselves directly affect cellular function. The human growth hormone (hGH)1 gene is expressed in epithelial cells of the normal human mammary gland. 2M. Raccurt, P. E. Lobie, E. Moudilou, S. Recher, T. Garcia-Caballero, L. Frappart, G. Morel, and H. C. Mertani, submitted for publication.2M. Raccurt, P. E. Lobie, E. Moudilou, S. Recher, T. Garcia-Caballero, L. Frappart, G. Morel, and H. C. Mertani, submitted for publication. Increased epithelial expression of the hGH gene is associated with the acquisition of pathological proliferation, and the highest level of hGH gene expression is observed in metastatic mammary carcinom" @default.
• W2041229746 created "2016-06-24" @default.
• W2041229746 creator A5037355737 @default.
• W2041229746 creator A5051119189 @default.
• W2041229746 creator A5051826848 @default.
• W2041229746 creator A5075820802 @default.
• W2041229746 creator A5091127998 @default.
• W2041229746 date "2002-07-01" @default.
• W2041229746 modified "2023-10-14" @default.
• W2041229746 title "Autocrine Human Growth Hormone Inhibits Placental Transforming Growth Factor-β Gene Transcription to Prevent Apoptosis and Allow Cell Cycle Progression of Human Mammary Carcinoma Cells" @default.
• W2041229746 cites W1905400971 @default.
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