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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Cell Line, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p21, Doxorubicin, Pancreatic Stellate Cells, RNA, Small Interfering, Rats, beta-Galactosidase.
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Is cdkn1a a key mediator of rat pancreatic stellate cell senescence? Context: Completion of pancreatic wound healing requires termination of pancreatic stellate cell (PSC) activation to prevent fibrosis. Besides induction of apoptosis and return to a quiescent phenotype, senescence of PSC followed by immune cell-mediated cytolysis represents a potential mechanism. Here, we have studied if the cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (Cdkn1a, p21/Waf1), expression of which is increased in senescent rat PSC, plays a causative role in the senescence process. Senescence was induced by doxorubicin treatment. The functions of Cdkn1a were analyzed using two approaches, treatment of primary rat PSC with siRNA and tetracycline-regulated overexpression of Cdkn1a in immortalized rat cells. Expression of senescence-associated β-galactosidase (SA β-Gal) was used as a surrogate marker of senescence. The knockdown of Cdkn1a significantly attenuated the growth-inhibitory effect of doxorubicin and strongly diminished the portion of SA β-Gal-positive cells. Overexpression of Cdkn1a enhanced both the antiproliferative effect of doxorubicin and induction of senescence. In primary PSC, doxorubicin treatment was associated with increased expression of interleukin-6 (IL-6) and matrix metalloproteinase (MMP)-9, while expression of the activation marker α-smooth muscle actin (α-SMA), p53, Cdk1 and Rad54 was diminished. The application of Cdkn1a siRNA specifically antagonized the effects of doxorubicin on the expression of p53, Cdk1 and Rad54 but not IL-6 and α-SMA, while MMP-9 expression and also activity were even enhanced.
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Cdkn1a plays a direct role in the process of rat PSC senescence. Additional Cdkn1a-independent pathways may contribute to the partial maintenance of a gene expression profile typical of senescent PSC. Final Decision: yes