p38 Kinase Regulates Nitric Oxide-induced Apoptosis of Articular Chondrocytes by Accumulating p53 via NFkappa B-dependent Transcription and Stabilization by Serine 15 Phosphorylation

S.-J. Kim
2002 Journal of Biological Chemistry  
Nitric oxide (NO) during primary culture of articular chondrocytes causes apoptosis via p38 mitogen-activated protein kinase in association with elevation of p53 protein level, caspase-3 activation, and differentiation status. In this study, we characterized the molecular mechanism by which p38 kinase induces apoptosis through activation of p53. We report here that NO-induced activation of p38 kinase leads to activation of NFB, which in turn induces transcription of the p53 gene. Activated p38
more » ... inase also physically associates and phosphorylates the serine 15 residue of p53, which results in accumulation of p53 protein during NO-induced apoptosis. Ectopic expression of wild-type p53 enhanced NO-induced apoptosis, whereas expression of a dominant negative p53 blocked it, indicating that p53 plays an essential role in NO-induced apoptosis of chondrocytes. The increased accumulation of p53 caused expression of Bax, a pro-apoptotic member of the Bcl-2 family that is known to cause apoptosis via release of cytochrome c and caspase activation. These results suggest that NO-activated p38 kinase activates p53 function in two different ways, transcriptional activation by NFB and direct phosphorylation of p53 protein, leading to apoptosis of articular chondrocytes.
doi:10.1074/jbc.m202862200 pmid:12091386 fatcat:ucfqgeq7une3pi532ym26dksjq