Sp3 is a ubiquitous transcription factor closely related to Sp1. Here we show that Sp3 is a target for SUMO modi®cation in vivo and in vitro. SUMO modi®cation of Sp3 occurs at a single lysine located between the second glutamine-rich activation domain and the DNA-binding domain. Mutational analyses identi®ed the sequence IKXE as essential for SUMO conjugation to Sp3. We identi®ed the protein inhibitor of activated STAT1 (PIAS1) as an interaction partner of Sp3 and Ubc9. Moreover, PIAS1 strongly stimulated SUMO conjugation to Sp3, thus acting as an E3 ligase for SUMO conjugation to Sp3. All mutations that prevented SUMO modi®cation in vitro strongly enhanced the transcriptional activity of Sp3, showing that SUMO modi®cation silences Sp3 activity. SUMOmodi®ed Sp3 bound to DNA with similar speci®city and af®nity as unmodi®ed Sp3. However, DNA-bound Sp3 did not act as a substrate for SUMO modi®cation.
Normal human prostatic (NHP) epithelial cells undergo senescence in vitro and in vivo, but little is known about the tissue-specific molecular mechanisms. Here we first characterize young primary NHP cells as CK5 þ /CK18 þ intermediate basal cells that also express several other putative stem/progenitor cell markers including p63, CD44, a2b1, and hTERT. When cultured in serum-and androgen-free medium, NHP cells gradually lose the expression of these markers, slow down in proliferation, and enter senescence. Several pieces of evidence implicate 15-lipoxygenase 2 (15-LOX2), a molecule with a restricted tissue expression and most abundantly expressed in adult human prostate, in the replicative senescence of NHP cells. First, the 15-LOX2 promoter activity and the mRNA and protein levels of 15-LOX2 and its multiple splice variants are upregulated in serially passaged NHP cells, which precede replicative senescence and occur in a cell-autonomous manner. Second, all immortalized prostate epithelial cells and prostate cancer cells do not express 15-LOX2. Third, PCa cells stably transfected with 15-LOX2 or 15-LOX2sv-b, a splice variant that does not possess arachidonate-metabolizing activity, show a passage-related senescence-like phenotype. Fourth, infection of early-passage NHP cells with retroviral vectors encoding 15-LOX2 or 15-LOX2sv-b induces partial cellcycle arrest and big and flat senescence-like phenotype. Finally, 15-LOX2 protein expression in human prostate correlates with age. Together, these data suggest that 15-LOX2 may represent an endogenous prostate senescence gene and its tumor-suppressing functions might be associated with its ability to induce cell senescence.
Endometrial cancer (EC) is the most common gynecologic malignancy of the female genital tract and the fourth most common neoplasia in women. In EC, myometrial invasion is considered one of the most important prognostic factors. For this process to occur, epithelial tumor cells need to undergo an epithelial to mesenchymal transition (EMT), either transiently or stably, and to differing degrees. This process has been extensively described in other types of cancer but has been poorly studied in EC. In this review, several features of EMT and the main molecular pathways responsible for triggering this process are investigated in relation to EC. The most common hallmarks of EMT have been found in EC, either at the level of E-cadherin loss or at the induction of its repressors, as well as other molecular alterations consistent with the mesenchymal phenotype-like L1CAM and BMI-1 up-regulation. Pathways including progesterone receptor, TGFβ, ETV5 and microRNAs are deeply related to the EMT process in EC.
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