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Inhibitor of differentiation 1 (Id1) promotes cell survival and proliferation of prostate epithelial cells
Cellular & Molecular Biology Letters volume 15, pages 272–295 (2010)
Abstract
Id1 (inhibitor of differentiation 1) is a member of the bHLH protein family. Consistent with its role in promoting proliferation and inhibiting differentiation, Id1 expression is low or negligible in normal prostate epithelial cells but is high in prostate cancer. Ectopic expression of Id1 in normal prostate epithelial cells could therefore provide a model for understanding early events involved in initiation of prostate cancer. Over-expression of Id1 immortalized but did not transform ventral prostate epithelial cells (Id1-RPE). Immortalization was associated with decreased Cdkn2a, Cdkn1a, androgen receptor and increased Tert expression. Gene expression profiling over successive doublings was used to identify transcriptomic changes involved during immortalization (Tieg, Jun, alpha actin, Klf10, Id2) and in maintaining the immortalized phenotype (Igfbp3, Igfbp5, Mmp2, Tgfb3). Network analysis indicated that Id1 promotes cancer/tumor morphology, cell cycle and epithelial to mesenchymal transition by influencing AP1, tnf, tgfβ, PdgfBB and estradiol pathways. During immortalization, the expression of majority of differentially expressed genes reduced over progressive doublings suggesting a decline in transcriptional regulatory mechanisms. The associated molecular/gene expression profile of Id1-RPE cells provides an opportunity to understand the molecular pathways associated with prostate epithelial cell survival and proliferation.
Abbreviations
- bHLH:
-
basic helix loop helix
- CDKI:
-
cyclin dependent kinase inhibitor
- EMT:
-
epithelial - mesenchymal transition
- HGF:
-
hepatocyte growth factor
- Id:
-
inhibitor of differentiation
- KGF:
-
keratinocyte growth factor
- MAPK:
-
mitogen activated protein kinase
- NHUC:
-
normal human urothelial cells
- PrEC:
-
prostate epithelial cells (human)
- R1881:
-
methyltrienolone (non-aromatizable synthetic androgen analogue)
- RPE:
-
rat prostate epithelial
- TERT:
-
telomerase reverse transcriptase
References
Norton, J.D., Deed, R.W., Craggs, G. and Sablitzky, F. Id helix-loop-helix proteins in cell growth and differentiation. Trends Cell. Biol. 8 (1998) 58–65.
Benezra, R., Davis, R.L., Lockshon, D., Turner, D.L. and Weintraub, H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell 61 (1990) 49–59.
Barone, M.V., Pepperkok, R., Peverali, F.A. and Philipson, L. Id proteins control growth induction in mammalian cells. Proc. Natl. Acad. Sci. USA 91 (1994) 4985–4988.
Hara, E., Yamaguchi, T., Nojima, H., Ide, T., Campisi, J., Okayama, H. and Oda, K. Id-related genes encoding helix-loop-helix proteins are required for G1 progression and are repressed in senescent human fibroblasts. J. Biol. Chem. 269 (1994) 2139–2145.
Coppe, J.P., Smith, A.P. and Desprez, P.Y. Id proteins in epithelial cells. Exp. Cell Res. 285 (2003) 131–145.
Israel, M.A., Hernandez, M.C., Florio, M., Andres-Barquin, P.J., Mantani, A., Carter, J.H. and Julin, C.M. Id gene expression as a key mediator of tumor cell biology. Cancer Res. 59 (1999) 1726s–1730s.
Norton, J.D. ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis. J. Cell Sci. 113 (Pt 22) (2000) 3897–3905.
Perk, J., Iavarone, A. and Benezra, R. Id family of helix-loop-helix proteins in cancer. Nat. Rev. Cancer 5 (2005) 603–614.
Ouyang, X.S., Wang, X., Lee, D.T., Tsao, S.W. and Wong, Y.C. Over expression of ID-1 in prostate cancer. J. Urol. 167 (2002) 2598–2602.
Forootan, S.S., Wong, Y.C., Dodson, A., Wang, X., Lin, K., Smith, P.H., Foster, C.S. and Ke, Y. Increased Id-1 expression is significantly associated with poor survival of patients with prostate cancer. Hum. Pathol. 38 (2007) 1321–1329.
Coppe, J.P., Itahana, Y., Moore, D.H., Bennington, J.L. and Desprez, P.Y. Id-1 and Id-2 proteins as molecular markers for human prostate cancer progression. Clin. Cancer Res. 10 (2004) 2044–2051.
Ling, M.T., Wang, X., Ouyang, X.S., Lee, T.K., Fan, T.Y., Xu, K., Tsao, S.W. and Wong, Y.C. Activation of MAPK signaling pathway is essential for Id-1 induced serum independent prostate cancer cell growth. Oncogene 21 (2002) 8498–8505.
Ling, M.T., Wang, X., Ouyang, X.S., Xu, K., Tsao, S.W. and Wong, Y.C. Id-1 expression promotes cell survival through activation of NF-kappaB signalling pathway in prostate cancer cells. Oncogene 22 (2003) 4498–4508.
Ling, M.T., Wang, X., Tsao, S.W. and Wong, Y.C. Down-regulation of Id-1 expression is associated with TGF beta 1-induced growth arrest in prostate epithelial cells. Biochim. Biophys. Acta 1570 (2002) 145–152.
Chaudhary, J., Schmidt, M. and Sadler-Riggleman, I. Negative acting HLH proteins Id 1, Id 2, Id 3, and Id 4 are expressed in prostate epithelial cells. Prostate 64 (2005) 253–264.
Ling, M.T., Wang, X., Lee, D.T., Tam, P.C., Tsao, S.W. and Wong, Y.C. Id-1 expression induces androgen-independent prostate cancer cell growth through activation of epidermal growth factor receptor (EGF-R). Carcinogenesis 25 (2004) 517–525.
Asirvatham, A.J., Schmidt, M.A. and Chaudhary, J. Non-redundant inhibitor of differentiation (Id) gene expression and function in human prostate epithelial cells. Prostate 66 (2006) 921–935.
Ouyang, X.S., Wang, X., Lee, D.T., Tsao, S.W. and Wong, Y.C. Upregulation of TRPM-2, MMP-7 and ID-1 during sex hormone-induced prostate carcinogenesis in the Noble rat. Carcinogenesis 22 (2001) 965–973.
Wice, B.M. and Gordon, J.I. Forced expression of Id-1 in the adult mouse small intestinal epithelium is associated with development of adenomas. J. Biol. Chem. 273 (1998) 25310–25319.
Alani, R.M., Hasskarl, J., Grace, M., Hernandez, M.C., Israel, M.A. and Munger, K. Immortalization of primary human keratinocytes by the helixloop-helix protein, Id-1. Proc. Natl. Acad. Sci. USA 96 (1999) 9637–9641.
Nickoloff, B.J., Chaturvedi, V., Bacon, P., Qin, J.Z., Denning, M.F. and Diaz, M.O. Id-1 delays senescence but does not immortalize keratinocytes. J. Biol. Chem. 275 (2000) 27501–27504.
Chaudhary, J., Sadler-Riggleman, I., Ague, J.M. and Skinner, M.K. The helix-loop-helix inhibitor of differentiation proteins induce post-mitotic terminally differentiated sertoli cells to re-enter the cell cycle and proliferate. Biol. Reprod. 72 (2005) 1205–1217.
Alani, R.M., Young, A.Z. and Shifflett, C.B. Id1 regulation of cellular senescence through transcriptional repression of p16/Ink4a. Proc. Natl. Acad. Sci. USA 98 (2001) 7812–7816.
Zheng, W., Wang, H., Xue, L., Zhang, Z. and Tong, T. Regulation of cellular senescence and p16(INK4a) expression by Id1 and E47 proteins in human diploid fibroblast. J. Biol. Chem. 279 (2004) 31524–31532.
Hasskarl, J., Duensing, S., Manuel, E. and Munger, K. The helix-loop-helix protein ID1 localizes to centrosomes and rapidly induces abnormal centrosome numbers. Oncogene 23 (2004) 1930–1938.
Man, C., Rosa, J., Yip, Y.L., Cheung, A.L., Kwong, Y.L., Doxsey, S.J. and Tsao, S.W. Id1 overexpression induces tetraploidization and multiple abnormal mitotic phenotypes by modulating aurora A. Mol. Biol. Cell 19 (2008) 2389–2401.
Schwarze, S.R., Shi, Y., Fu, V.X., Watson, P.A. and Jarrard, D.F. Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. Oncogene 20 (2001) 8184–8192.
Peehl, D.M. Primary cell cultures as models of prostate cancer development. Endocr. Relat. Cancer 12 (2005) 19–47.
Chowdhury, A., Harber, G.J. and Chopra, D.P. Characterization and serial propagation of mouse prostate epithelial cells in serum-free medium. Biol. Cell 67 (1989) 281–287.
Asirvatham, A.J., Schmidt, M., Gao, B. and Chaudhary, J. Androgens regulate the immune/inflammatory response and cell survival pathways in rat ventral prostate epithelial cells. Endocrinology 147 (2006) 257–271.
Schwarze, S.R., DePrimo, S.E., Grabert, L.M., Fu, V.X., Brooks, J.D. and Jarrard, D.F. Novel pathways associated with bypassing cellular senescence in human prostate epithelial cells. J. Biol. Chem. 277 (2002) 14877–14883.
Fujimoto, N., Suzuki, T., Honda, H. and Kitamura, S. Estrogen enhancement of androgen-responsive gene expression in hormone-induced hyperplasia in the ventral prostate of F344 rats. Cancer Sci. 95 (2004) 711–715.
Homma, Y., Kondo, Y., Kaneko, M., Kitamura, T., Nyou, W.T., Yanagisawa, M., Yamamoto, Y. and Kakizoe, T. Promotion of carcinogenesis and oxidative stress by dietary cholesterol in rat prostate. Carcinogenesis 25 (2004) 1011–1014.
Prins, G.S., Birch, L. and Greene, G.L. Androgen receptor localization in different cell types of the adult rat prostate. Endocrinology 129 (1991) 3187–3199.
Rhim, J.S. Research into molecular and genetic mechanisms underlying prostate carcinogenesis would be greatly advanced by in vitro prostate cell models. Drugs Today (Barc) 39 (2003) 837–847.
Cussenot, O., Berthon, P., Cochand-Priollet, B., Maitland, N.J. and Le Duc, A. Immunocytochemical comparison of cultured normal epithelial prostatic cells with prostatic tissue sections. Exp. Cell Res. 214 (1994) 83–92.
Ilio, K.Y., Sensibar, J.A. and Lee, C. Effect of TGF-beta 1, TGF-alpha, and EGF on cell proliferation and cell death in rat ventral prostatic epithelial cells in culture. J. Androl. 16 (1995) 482–490.
Itoh, N., Patel, U. and Skinner, M.K. Developmental and hormonal regulation of transforming growth factor-alpha and epidermal growth factor receptor gene expression in isolated prostatic epithelial and stromal cells. Endocrinology 139 (1998) 1369–1377.
Shibuki, H., Katai, N., Kuroiwa, S., Kurokawa, T., Arai, J., Matsumoto, K., Nakamura, T. and Yoshimura, N. Expression and neuroprotective effect of hepatocyte growth factor in retinal ischemia-reperfusion injury. Invest. Ophthalmol. Vis. Sci. 43 (2002) 528–536.
Sugimura, Y., Foster, B.A., Hom, Y.K., Lipschutz, J.H., Rubin, J.S., Finch, P.W., Aaronson, S.A., Hayashi, N., Kawamura, J. and Cunha, G.R. Keratinocyte growth factor (KGF) can replace testosterone in the ductal branching morphogenesis of the rat ventral prostate. Int. J. Dev. Biol. 40 (1996) 941–951.
Gmyrek, G.A., Walburg, M., Webb, C.P., Yu, H.M., You, X., Vaughan, E.D., Vande Woude, G.F. and Knudsen, B.S. Normal and malignant prostate epithelial cells differ in their response to hepatocyte growth factor/scatter factor. Am. J. Pathol. 159 (2001) 579–590.
Tang, J., Gordon, G.M., Nickoloff, B.J. and Foreman, K.E. The helix-loop-helix protein id-1 delays onset of replicative senescence in human endothelial cells. Lab. Invest. 82 (2002) 1073–1079.
Reddel, R.R. The role of senescence and immortalization in carcinogenesis. Carcinogenesis 21 (2000) 477–484.
Hahn, W.C. Immortalization and transformation of human cells. Mol. Cells 13 (2002) 351–361.
McConnell, B.B., Starborg, M., Brookes, S. and Peters, G. Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts. Curr. Biol. 8 (1998) 351–354.
Shao, G., Balajee, A.S., Hei, T.K. and Zhao, Y. p16(INK4a) downregulation is involved in immortalization of primary human prostate epithelial cells induced by telomerase. Mol. Carcinog. 47 (2008) 775–783.
Chapman, E.J., Hurst, C.D., Pitt, E., Chambers, P., Aveyard, J.S. and Knowles, M.A. Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway. Oncogene 25 (2006) 5037–5045.
Iavarone, A., Garg, P., Lasorella, A., Hsu, J. and Israel, M.A. The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein. Genes Dev. 8 (1994) 1270–1284.
Lasorella, A., Iavarone, A. and Israel, M.A. Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins. Mol. Cell. Biol. 16 (1996) 2570–2578.
Zenzmaier, C., Untergasser, G., Hermann, M., Dirnhofer, S., Sampson, N. and Berger, P. Dysregulation of Dkk-3 expression in benign and malignant prostatic tissue. Prostate 68 (2008) 540–547.
Kawano, Y., Kitaoka, M., Hamada, Y., Walker, M.M., Waxman, J. and Kypta, R.M. Regulation of prostate cell growth and morphogenesis by Dickkopf-3. Oncogene 25 (2006) 6528–6537.
Tsuji, T., Miyazaki, M., Sakaguchi, M., Inoue, Y. and Namba, M. A REIC gene shows down-regulation in human immortalized cells and human tumor-derived cell lines. Biochem. Biophys. Res. Commun. 268 (2000) 20–24.
Kashiwakura, Y., Ochiai, K., Watanabe, M., Abarzua, F., Sakaguchi, M., Takaoka, M., Tanimoto, R., Nasu, Y., Huh, N.H. and Kumon, H. Down-regulation of inhibition of differentiation-1 via activation of activating transcription factor 3 and Smad regulates REIC/Dickkopf-3-induced apoptosis. Cancer Res. 68 (2008) 8333–8341.
Damdinsuren, B., Nagano, H., Kondo, M., Natsag, J., Hanada, H., Nakamura, M., Wada, H., Kato, H., Marubashi, S., Miyamoto, A., Takeda, Y., Umeshita, K., Dono, K. and Monden, M. TGF-beta1-induced cell growth arrest and partial differentiation is related to the suppression of Id1 in human hepatoma cells. Oncol. Rep. 15 (2006) 401–408.
Ling, M.T., Lau, T.C., Zhou, C., Chua, C.W., Kwok, W.K., Wang, Q., Wang, X. and Wong, Y.C. Overexpression of Id-1 in prostate cancer cells promotes angiogenesis through the activation of vascular endothelial growth factor (VEGF). Carcinogenesis 26 (2005) 1668–1676.
Li, Y., Yang, J., Luo, J.H., Dedhar, S. and Liu, Y. Tubular epithelial cell dedifferentiation is driven by the helix-loop-helix transcriptional inhibitor Id1. J. Am. Soc. Nephrol. 18 (2007) 449–460.
Goossens, K., Deboel, L., Swinnen, J.V., Roskams, T., Manin, M., Rombauts, W. and Verhoeven, G. Both retinoids and androgens are required to maintain or promote functional differentiation in reaggregation cultures of human prostate epithelial cells. Prostate 53 (2002) 34–49.
Grant, E.S., Batchelor, K.W. and Habib, F.K. Androgen independence of primary epithelial cultures of the prostate is associated with a down-regulation of androgen receptor gene expression. Prostate 29 (1996) 339–349.
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Schmidt, M., Asirvatham, A.J. & Chaudhary, J. Inhibitor of differentiation 1 (Id1) promotes cell survival and proliferation of prostate epithelial cells. Cell Mol Biol Lett 15, 272–295 (2010). https://doi.org/10.2478/s11658-010-0007-3
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DOI: https://doi.org/10.2478/s11658-010-0007-3