Minireview: Physiological and Pathological Actions of RAS in the Ovary

Overview

Journal Mol Endocrinol

Specialties Endocrinology
Molecular Biology

Date 2009 Nov 3

PMID 19880654

Citations 21

Authors

Heng-Yu Fan

JoAnne S Richards

Affiliations

Soon will be listed here.

Abstract

The small G proteins of the RAS superfamily act as molecular switches in the transduction of cellular signals critical for a wide range of normal developmental events as well as pathological processes. However, the functions of Ras genes in ovarian cells have only started to be unveiled. RAS, most likely KRAS that is highly expressed in granulosa cells of growing follicles, appears crucial for mediating the gonadotropin-induced events associated with the unique physiological process of ovulation. By contrast, conditional expression of a constitutively active Kras(G12D) mutant in granulosa cells results in ovulation defects due to the complete disruption of normal follicular growth, cessation of granulosa cell proliferation, and blockage of granulosa cell apoptosis and differentiation. When the tumor suppressor Pten is disrupted conditionally in the Kras(G12D)-expressing granulosa cells, granulosa cell tumors fail to develop. However, ovarian surface epithelial cells expressing the same Pten;Kras(G12D) mutations rapidly become ovarian surface epithelial serous cystadenocarcinomas. In this minireview, we summarize some of the physiological as well as pathological functions of RAS in the rodent ovary, discuss the implications of the Kras(G12D) mutant mouse models for understanding human diseases such as premature ovarian failure and ovarian cancers, and highlight new questions raised by the results of recent studies.

Citing Articles

A Cross-Sectional Exploratory Study of Rat Sarcoid (Ras) Activation in Women with and Without Polycystic Ovary Syndrome.

Niinuma S, Habib H, Takemoto A, Das P, Sathyapalan T, Atkin S Cells. 2025; 14(5).

PMID: 40072105 PMC: 11898917. DOI: 10.3390/cells14050377.

Aberrant activation of KRAS in mouse theca-interstitial cells results in female infertility.

Sun P, Wang H, Liu L, Guo K, Li X, Cao Y Front Physiol. 2022; 13:991719.

PMID: 36060690 PMC: 9437434. DOI: 10.3389/fphys.2022.991719.

Changes in Transcriptomic Profiles in Different Reproductive Periods in Yaks.

Guo S, Cao M, Wang X, Xiong L, Wu X, Bao P Biology (Basel). 2021; 10(12).

PMID: 34943144 PMC: 8698885. DOI: 10.3390/biology10121229.

Folliculogenesis in Mammalian Models: A Computational Biology Study.

Bernabo N, Di Berardino C, Capacchietti G, Peserico A, Buoncuore G, Tosi U Front Mol Biosci. 2021; 8:737912.

PMID: 34859047 PMC: 8630647. DOI: 10.3389/fmolb.2021.737912.

The Role of the Guanosine Nucleotide-Binding Protein in the Corpus Luteum.

Billhaq D, Lee S Animals (Basel). 2021; 11(6).

PMID: 34073800 PMC: 8225084. DOI: 10.3390/ani11061524.

References

Mantena S, Kannan A, Cheon Y, Li Q, Johnson P, Bagchi I . C/EBPbeta is a critical mediator of steroid hormone-regulated cell proliferation and differentiation in the uterine epithelium and stroma. Proc Natl Acad Sci U S A. 2006; 103(6):1870-5. PMC: 1413629. DOI: 10.1073/pnas.0507261103. View

Hall A . Ras-related proteins. Curr Opin Cell Biol. 1993; 5(2):265-8. DOI: 10.1016/0955-0674(93)90114-6. View

Sterneck E, Tessarollo L, Johnson P . An essential role for C/EBPbeta in female reproduction. Genes Dev. 1997; 11(17):2153-62. PMC: 275394. DOI: 10.1101/gad.11.17.2153. View

Cantley L, Neel B . New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A. 1999; 96(8):4240-5. PMC: 33561. DOI: 10.1073/pnas.96.8.4240. View

Matzuk M, Burns K, Viveiros M, Eppig J . Intercellular communication in the mammalian ovary: oocytes carry the conversation. Science. 2002; 296(5576):2178-80. DOI: 10.1126/science.1071965. View

Kumar T, Low M, Matzuk M . Genetic rescue of follicle-stimulating hormone beta-deficient mice. Endocrinology. 1998; 139(7):3289-95. DOI: 10.1210/endo.139.7.6111. View

Soyal S, Mukherjee A, Lee K, Li J, Li H, DeMayo F . Cre-mediated recombination in cell lineages that express the progesterone receptor. Genesis. 2005; 41(2):58-66. DOI: 10.1002/gene.20098. View

Lague M, Paquet M, Fan H, Kaartinen M, Chu S, Jamin S . Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression. Carcinogenesis. 2008; 29(11):2062-72. PMC: 2577137. DOI: 10.1093/carcin/bgn186. View

Bliss S, Miller A, Navratil A, Xie J, McDonough S, Fisher P . ERK signaling in the pituitary is required for female but not male fertility. Mol Endocrinol. 2009; 23(7):1092-101. PMC: 2703601. DOI: 10.1210/me.2009-0030. View

10.

Krimpenfort P, Ijpenberg A, Song J, van der Valk M, Nawijn M, Zevenhoven J . p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a. Nature. 2007; 448(7156):943-6. DOI: 10.1038/nature06084. View

11.

Erdogan M, Pozzi A, Bhowmick N, Moses H, Zent R . Signaling pathways regulating TC21-induced tumorigenesis. J Biol Chem. 2007; 282(38):27713-20. DOI: 10.1074/jbc.M703037200. View

12.

Connolly D, Bao R, Nikitin A, Stephens K, Poole T, Hua X . Female mice chimeric for expression of the simian virus 40 TAg under control of the MISIIR promoter develop epithelial ovarian cancer. Cancer Res. 2003; 63(6):1389-97. View

13.

Serrano M, Lin A, McCurrach M, Beach D, Lowe S . Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997; 88(5):593-602. DOI: 10.1016/s0092-8674(00)81902-9. View

14.

Richards J, Sharma S, Falender A, Lo Y . Expression of FKHR, FKHRL1, and AFX genes in the rodent ovary: evidence for regulation by IGF-I, estrogen, and the gonadotropins. Mol Endocrinol. 2002; 16(3):580-99. DOI: 10.1210/mend.16.3.0806. View

15.

Boerboom D, White L, Dalle S, Courty J, Richards J . Dominant-stable beta-catenin expression causes cell fate alterations and Wnt signaling antagonist expression in a murine granulosa cell tumor model. Cancer Res. 2006; 66(4):1964-73. DOI: 10.1158/0008-5472.CAN-05-3493. View

16.

Fan H, Liu Z, Cahill N, Richards J . Targeted disruption of Pten in ovarian granulosa cells enhances ovulation and extends the life span of luteal cells. Mol Endocrinol. 2008; 22(9):2128-40. PMC: 2631369. DOI: 10.1210/me.2008-0095. View

17.

Koera K, Nakamura K, Nakao K, Miyoshi J, Toyoshima K, Hatta T . K-ras is essential for the development of the mouse embryo. Oncogene. 1997; 15(10):1151-9. DOI: 10.1038/sj.onc.1201284. View

18.

Tuveson D, Shaw A, Willis N, Silver D, Jackson E, Chang S . Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell. 2004; 5(4):375-87. DOI: 10.1016/s1535-6108(04)00085-6. View

19.

Hsieh M, Lee D, Panigone S, Horner K, Chen R, Theologis A . Luteinizing hormone-dependent activation of the epidermal growth factor network is essential for ovulation. Mol Cell Biol. 2006; 27(5):1914-24. PMC: 1820474. DOI: 10.1128/MCB.01919-06. View

20.

Sebastian T, Johnson P . Stop and go: anti-proliferative and mitogenic functions of the transcription factor C/EBPbeta. Cell Cycle. 2006; 5(9):953-7. DOI: 10.4161/cc.5.9.2733. View