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ical processes of p53 Regulates Differentiation 10 p53 Regulates Differentiation levels for osterix and osteocalcin were determined by QRT-PCR. The results of QRT-PCR are presented as a range of two duplicate runs after normalization to HPRT control. C2-sh-p53 and C2-sh-con cells were grown in culture for 48 h, then medium was changed to condition medium from 293T cells overexpressing BMP4 protein. Osteogenic differentiation was assessed by measuring ALP activity and Alizarin Red staining for Ca2+ precipitates. doi:10.1371/journal.pone.0003707.g007 cell growth and differentiation. Here we demonstrate that p53 inhibits not only osteogenesis as already shown before in other experimental systems, but also serve as an inhibitor of adipogenesis and myofibroblast differentiation of both human and mouse fibroblasts, and of mouse bone marrow stromal cells. In contrast to this broad inhibitory activity, p53 is required for differentiation of skeletal muscle cells GW788388 site towards mature 23727046 myofibers or osteoblasts. The involvement of p53 in osteogenesis was recently reported by several groups. Two independent studies have addressed the role of p53 in mouse differentiation models and have established that p53 functions as a negative regulator of osteoblast differentiation in-vivo and in-vitro we provide compelling evidence that p53 inhibits adipogenesis in vitro. Our findings that p53 represses expression of the key adipogenic transcription factors PPARc and CEBPa might represent a mechanistic basis for this effect. Although PPARc plays a central role, as both necessary and sufficient factor during adipogenesis, there are more than one hundred other transcription factors that are expressed in adipocytes. Therefore, the fact that the PPARc antagonist, GW9662, completely blocked the accelerated adipogenic differentiation of sh-p53 MEFs, suggests that p53 might exert its inhibitory effect through this upstream key regulator of adipocyte differentiation. In addition to 15976016 its function as a regulator of adipocytes differentiation, PPARc is expressed by several other tissues, and is involved in a number of pathological processes, such as inflammation and cancer. It was found to be highly expressed by normal colonic mucosa, colorectal adenocarcinomas, and colon cancer cell lines. Mice treated with a PPARc ligand have greater number of polyps in the colon, and the levels of PPARc mRNA in tumors of colorectal cancer patients were higher than those in adjacent normal colonic mucosa. We observed upregulation of PPARc mRNA in the colon of part of p53 null mice compared to their wt littermates. Due to the incomplete penetrance of the p53 null phenotype, a larger group of mice should be tested to verify the specific effect of p53 deficiency on PPARc expression, in vivo. Thus, while the lack of p53 in cells that can give rise to adipocytes leads to their terminal adipogenic differentiation, p53 deficiency that may lead to upregulation of PPARc expression in colonic epithelial cells could result in their neoplastic transformation. This suggests a complex and/or indirect mechanism linking p53 and PPARc. Osteoblasts and adipocytes are derived from multipotent marrow mesenchymal cells, which express low levels of both adipogenic and osteogenic factors. Factors of one lineage repress factors of the other lineage, thereby maintaining the undifferentiated state of these cells. Commitment of marrow mesenchymal cells towards one of these lineages occurs when this balance is tipped lea

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Author: calcimimeticagent