Abstract
ABSTRACTHyaluronan, p53, and transforming growth factor‐β1 (TGF‐β1) play important roles in skin function. They are involved in keratinocyte growth, migration, and differentiation, although the way they interact is not well understood. Analysis of p63 genome‐wide chromatin immunoprecipitation and sequencing (ChIP‐seq) revealed that ΔNp63, a paralogue of p53, binds to the genomic loci of HAS2 and HAS3, encoding hyaluronan synthases, in human‐immortalized keratinocyte HaCaT cells which express mutant p53. Additionally, ΔNp63 binding to these loci, particularly onto the HAS2 gene, was further increased by constitutively active (ca)RAS‐ and TGF‐β1‐mediated suppression of p53. We found that p53 suppressed HAS2 and HAS3 mRNA expression, while ΔNp63 increased their expression. When mutant p53 was silenced, there was a significant increase in HAS2 and HAS3 expression in unstimulated HaCaT cells. After TGF‐β1 stimulation, HAS2 expression was further increased while HAS3 expression was suppressed. Additionally, p53 mutation and abrogation affected the levels of secreted hyaluronan. Moreover, activation of RAS played a key role in regulating TGF‐β1‐mediated expression of HAS2 and the hyaluronan receptor CD44 in a cell‐specific manner. The level of HAS3 was associated with the malignant phenotype in the MCF10A breast cancer progression model. In conclusion, we found that endogenous p53 and ΔNp63 activities are pivotal in regulating HAS2 and HAS3 mRNA expression in connection to TGF‐β1 stimulation and RAS activation.
Published Version
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