TAp63-dependent induction of growth differentiation factor 15 (GDF15) plays a critical role in the regulation of keratinocyte differentiation.

Since p63-deficient mice display severe defects in formation of epidermis, p63 has been considered to be a multi-isoform p53 family member essential for epidermal development. However, it is still unclear how p63 could contribute to keratinocyte differentiation. In the present study, we have found that TAp63alpha is induced in association with the upregulation and a secretion of growth differentiation factor 15 (GDF15) during the keratinocyte differentiation of HaCaT cells bearing p53 mutation. Short interference RNA-mediated knockdown of the endogenous TAp63 resulted in a remarkable reduction of GDF15. Luciferase reporter assay and reverse transcription-PCR analysis demonstrated that enforced expression of TAp63alpha significantly increases the luciferase activity driven by GDF15 promoter and the expression of GDF15. Consistent with these results, the proximal p53/p63-binding site within the GDF15 promoter region was required for the TAp63alpha-mediated transcriptional activation of GDF15, and TAp63alpha was recruited onto this site. Furthermore, siRNA-mediated knockdown of the endogenous GDF15 permitted cell growth and inhibited the expression of the differentiation markers such as keratin 10 and involucrin in response to differentiation stimuli. Taken together, our present results provide a novel insight into understanding the molecular mechanisms behind TAp63alpha-mediated keratinocyte differentiation.