Functional interplay between p63 and p53 controls RUNX1 function in the transition from proliferation to differentiation in human keratinocytes

The interfollicular epidermis is continuously renewed, thanks to a regulated balance between proliferation and differentiation. The Delta Np63 transcription factor has a key role in the control of this process. It has been shown that Delta Np63 directly regulates Runt-related transcription factor 1 (RUNX1) transcription factor expression in mouse keratinocytes. The present study showed for the first time that RUNX1 is expressed in normal human interfollicular epidermis and that its expression is tightly regulated during the transition from proliferation to differentiation. It demonstrated that Delta Np63 directly binds two different RUNX1 regulatory DNA sequences and modulates RUNX1 expression differentially in proliferative or differentiated human keratinocytes. It also showed that the regulation of RUNX1 expression by Delta Np63 is dependent on p53 and that this coregulation relies on differential binding and activation of RUNX1 regulatory sequences by Delta Np63 and p53. We also found that RUNX1 inhibits keratinocyte proliferation and activates directly the expression of KRT1, a critical actor in early keratinocyte differentiation. Finally, we described that RUNX1 expression, similar to Delta Np63 and p53, was strongly expressed and downregulated in basal cell carcinomas and squamous cell carcinomas respectively. Taken together, these data shed light on the importance of tight control of the functional interplay between Delta Np63 and p53 in regulating RUNX1 transcription factor expression for proper regulation of interfollicular epidermal homeostasis. Cell Death and Disease (2012) 3, e318; doi:10.1038/cddis.2012.62; published online 7 June 2012