Rapid, nongenomic membranal effects of progesterone were demonstrated in amphibian oocytes more than 30 y ago. Recently, a distinct family of membrane progestin receptors (mPRs) has been cloned in fish and other vertebrate species. In this study we explore the role of mPR in promoting oocyte maturation in Xenopus laevis. RT-PCR analysis indicates that Xenopus oocytes contain transcripts for the mPRbeta ortholog, similar to what has been reported in zebrafish oocytes, and Western blotting shows that the protein is expressed on the oocyte plasma membrane. Microinjection of mPRbeta-specific antibodies into oocytes resulted in a dramatic inhibition of progesterone-dependent oocyte maturation, whereas microinjection of mRNA encoding Myc-Xenopus mPR (XmPR)beta resulted in an accelerated rate of progesterone-induced oocyte maturation, concomitant with membranal localization of the protein. Binding studies in mammalian cells expressing XmPRbeta confirmed specific binding of progesterone by the expressed protein. These results suggest that XmPRbeta is a physiological progesterone receptor involved in initiating the resumption of meiosis during maturation of Xenopus oocytes.

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Multiple Myeloma (MM) is a lymphatic neoplasm characterized by clonal proliferation of malignant plasma cell that eventually develops resistance to chemotherapy. Drug resistance, differentiation block and increased survival of the MM tumor cells result from high genomic instability. Chromosomal translocations, the most common genomic alterations in MM, lead to dysregulation of cyclin D, a regulatory protein that governs the activation of key cell cycle regulator – cyclin dependent kinase (CDK). Genomic instability was reported to be affected by over expression of another CDK regulator - cyclin E (CCNE). This occurs early in tumorigenesis in various lymphatic malignancies including CLL, NHL and HL. We therefore sought to investigate the role of cyclin E in MM. CCNE1 expression was found to be heterogeneous in various MM cell lines (hMMCLs). Incubation of hMMCLs with seliciclib, a selective CDK-inhibitor, results in apoptosis which is accompanied by down regulation of MCL1 and p27. Ectopic over expression of CCNE1 resulted in reduced sensitivity of the MM tumor cells in comparison to the paternal cell line, whereas CCNE1 silencing with siRNA increased the cell sensitivity to seliciclib. Adhesion to FN of hMMCLs was prevented by seliciclib, eliminating adhesion–mediated drug resistance of MM cells. Combination of seliciclib with flavopiridol effectively reduced CCNE1 and CCND1 protein levels, increased subG1 apoptotic fraction and promoted MM cell death in BMSCs co-culture conditions, therefore over-coming stroma-mediated protection. We suggest that seliciclib may be considered as essential component of modern anti MM drug combination therapy.