Progesterone-Induced Cyclin G1 Inhibits the Proliferation of Endometrial Epithelial Cell and its Possible Molecular Mechanism

Abstract

Under normal conditions, progesterone inhi­bits the estrogen-induced proliferation of endometrial epithelium. Our previous studies have shown that cyclin G1 was progesterone-dependent in mouse endometrial epithelium at peri-implantation, and exogenous cyclin G1 suppressed the proliferation of endometrial cancer cells. The objectives of this study are to determine whether cyclin G1, as a negative regulator of the cell cycle, is involved in the antiproliferative action of progesterone on endometrial epithelial cells, and to explore the possible molecular mechanism of cyclin G1 inhibition. The siRNA-mediated elimination of cyclin G1 attenuated the antiproliferative action of progesterone on endometrial epithelial cells. Immunoprecipitation showed that progesterone-induced cyclin G1 could interact with PP2A to mediate its phosphatase activity. The block of PP2A activity also attenuated the antiproliferative action of progesterone on endometrial epithelial cells and increased the phosphorylated Rb. In conclusion, progesterone-induced cyclin G1 mediates the inhibitory effect of progesterone on endometrial epithelial cell proliferation possibly through the recruitment of PP2A to dephosphorylate Rb.

Key words

cyclin G1 - progesterone - endometrial epithelial cells - protein phosphatase 2A - retinoblastoma tumor ­suppressor protein

^* These authors contributed equally to this work.

• References

• 1 Graham JD, Clarke CL. Physiological action of progesterone in target tissues. Endocr Rev 1997; 18: 502-519
• 2 Kim JJ, Chapman-Davis E. Role of progesterone in endometrial cancer. Semin Reprod Med 2010; 28: 81-90
• 3 Sherr CJ. Cancer cell cycles. Science 1996; 274: 1672-1677
• 4 Altucci L, Addeo R, Cicatiello L, Germano D, Pacilio C, Battista T, Cancemi M, Petrizzi VB, Bresciani F, Weisz A. Estrogen induces early and timed activation of cyclin-dependent kinases 4, 5, and 6 and increases cyclin messenger ribonucleic acid expression in rat uterus. Endocrinology 1997; 138: 978-984
• 5 Chen B, Pan H, Zhu L, Deng Y, Pollard JW. Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase-->AKT-->GSK-3beta-->cyclin D1→pRB pathway to block uterine epithelial cell proliferation. Mol Endocrinol 2005; 19: 1978-1990
• 6 Shiozawa T, Horiuchi A, Kato K, Obinata M, Konishi I, Fujii S, Nikaido T. Up-regulation of p27Kip1 by progestins is involved in the growth suppression of the normal and malignant human endometrial glandular cells. Endocrinology 2001; 142: 4182-4188
• 7 Jensen MR, Factor VM, Fantozzi A, Helin K, Huh CG, Thorgeirsson SS. Reduced hepatic tumor incidence in cyclin G1-deficient mice. Hepatology 2003; 37: 862-870
• 8 Wu L, Liu L, Yee A, Carbonarohall D, Tolo V, Hall F. Molecular-cloning of the human cycg1 gene encoding a g-type cyclin – overexpression in human osteosarcoma cells. Oncol Rep 1994; 1: 705-711
• 9 Gordon EM, Liu PX, Chen ZH, Liu L, Whitley MD, Gee C, Groshen S, Hinton DR, Beart RW, Hall FL. Inhibition of metastatic tumor growth in nude mice by portal vein infusions of matrix-targeted retroviral vectors bearing a cytocidal cyclin G1 construct. Cancer Res 2000; 60: 3343-3347
• 10 Zhao L, Samuels T, Winckler S, Korgaonkar C, Tompkins V, Horne MC, Quelle DE. Cyclin G1 has growth inhibitory activity linked to the ARF-Mdm2-p53 and pRb tumor suppressor pathways. Mol Cancer Res 2003; 1: 195-206
• 11 Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS, Prives C. Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell 2002; 9: 761-771
• 12 Yue L, Daikoku T, Hou X, Li M, Wang H, Nojima H, Dey SK, Das SK. Cyclin G1 and cyclin G2 are expressed in the periimplantation mouse uterus in a cell-specific and progesterone-dependent manner: evidence for aberrant regulation with Hoxa-10 deficiency. Endocrinology 2005; 146: 2424-2433
• 13 Liu F, Gao X, Yu H, Yuan D, Zhang J, He Y, Yue L. Effects of expression of exogenous cyclin G1 on proliferation of human endometrial carcinoma cells. Chin J Physiol 2013; 56: 83-89
• 14 Kover K, Liang L, Andrews GK, Dey SK. Differential expression and regulation of cytokine genes in the mouse uterus. Endocrinology 1995; 136: 1666-1673
• 15 Hanekamp EE, Kuhne LM, Grootegoed JA, Burger CW, Blok LJ. Progesterone receptor A and B expression and progestagen treatment in growth and spread of endometrial cancer cells in nude mice. Endocr Relat Cancer 2004; 11: 831-841
• 16 Boudreau RT, Hoskin DW. The use of okadaic acid to elucidate the intracellular role(s) of protein phosphatase 2A: lessons from the mast cell model system. Int Immunopharmacol 2005; 5: 1507-1518
• 17 Kanaoka Y, Kimura SH, Okazaki I, Ikeda M, Nojima H. GAK: a cyclin G associated kinase contains a tensin/auxilin-like domain. FEBS Lett 1997; 402: 73-80
• 18 Janssens V, Goris J. Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 2001; 353: 417-439
• 19 Kolupaeva V, Janssens V. PP1 and PP2A phosphatases – cooperating partners in modulating retinoblastoma protein activation. FEBS J 2013; 280: 627-643
• 20 Das RM, Martin L. Progesterone inhibition of mouse uterine epithelial proliferation. J Endocrinol 1973; 59: 205-206