ΔNp63α modulates phosphorylation of p38 MAP kinase in regulation of cell cycle progression and cell growth.

Abstract p53-related p63 plays a critical role in regulation of cell proliferation, survival and cell differentiation. Dysregulation of p63 functions results in a disruption of a variety of normal biological processes, including stem cell biology, embryonic development, aging and tumorigenesis. ΔNp63α, a predominantly expressed p63 protein isoform in epithelial cells, plays a crucial role in regulation of cell cycle progression and cell growth. p38 MAP kinases (p38MAPK) are the members of mitogen-activated protein kinases family and are critical in regulation of cell survival in response to stress signals. In this study, we show that ectopic expression of ΔNp63α inhibited phosphorylation of p38MAPK. Acute knockdown of p63 led to a significant upregulation of p38MAPK phosphorylation, resulting in increased p21cip1/waf1 expression, reduced phosphorylation of retinoblastoma protein (RB), cell cycle G1 arrest and cell growth retardation. Restoration of ΔNp63α expression reversed cell cycle arrest and growth inhibition induced by p63 ablation. Pharmacological inhibition of p38MAPK significantly suppressed ΔNp63α ablation-induced cell cycle G1/S arrest. In addition, MAP Kinase Phosphatase 3 (MKP3) was responsible for ΔNp63α-mediated regulation of p38MAPK phosphorylation. Together, these results suggest that ΔNp63α-MPK3-p38MAPK signaling pathway plays an important role in cell cycle progression and cell growth. Highlights The major highlights of this manuscript are: 1. ΔNp63α regulates phosphorylation of p38MAPK. Based on our knowledge, this is a first report in the field. 2. Ablation of ΔNp63α leads to cell cycle arrest and growth retardation, due to, in part, upregulation of p38MAPK phosphorylation and activation. 3. MAP Kinase Phosphatase 3 (MKP3) is responsible for ΔNp63α ablation-induced upregulation of p38MAPK phosphorylation. [ABSTRACT FROM AUTHOR]