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Wild-Type p53 Protein Is Up-Regulated upon Cyclic Adenosine Monophosphate-Induced Differentiation of Human Endometrial Stromal Cells

Institute for Hormone and Fertility Research (Y.P., J.F.), University of Hamburg, and Endokrinologikum Hamburg (T.S.-M., R.K., B.G.), 20251 Hamburg, Germany; Institute of Reproductive and Developmental Biology (M.C., J.J.B.), Imperial College London, Hammersmith Hospital, London W12 ONN, United Kingdom; and Department of Gynecopathology (K.M.-L.), Institute of Pathology, University Hospital of Hamburg, 20246 Hamburg, Germany

Address all correspondence and requests for reprints to: Birgit Gellersen, Ph.D., Endokrinologikum Hamburg, Falkenried 88, 20251 Hamburg, Germany. E-mail: gellersen{at}endokrinologikum.com.

Decidualization of the endometrial stromal compartment is critical for embryo implantation. Initiation of this differentiation process requires elevated intracellular cAMP levels. We now report a massive and sustained up-regulation of p53 tumor suppressor protein during cAMP-induced decidualization of cultured endometrial stromal cells. Nuclear accumulation of p53 was not accompanied by increased mRNA expression, suggesting stabilization of the protein as the underlying mechanism. Proteasomal degradation of p53 is known to be mediated by nuclear Mdm2. Nuclear translocation of Mdm2, in turn, is dependent on phosphorylation by protein kinase B/Akt (PKB/Akt). In cAMP-treated decidualized cells, p53 accumulation was associated with decreased nuclear Mdm2 and cytoplasmic PKB/Akt levels. Conversely, withdrawal of the decidualization stimulus resulted in morphological and biochemical dedifferentiation, disappearance of p53, but increased abundance of PKB/Akt. Furthermore, Western blot and immunohistochemical analyses of endometrial biopsies confirmed that p53 is expressed in vivo in the stromal compartment during the late secretory phase of the cycle. The observation that p53 protein expression is closely associated with decidual transformation indicates a novel role for this tumor suppressor in regulating human endometrial function.

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