Abstract
The interfollicular epidermis is continuously renewed, thanks to a regulated balance between proliferation and differentiation. The ΔNp63 transcription factor has a key role in the control of this process. It has been shown that ΔNp63 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 ΔNp63 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 ΔNp63 is dependent on p53 and that this coregulation relies on differential binding and activation of RUNX1 regulatory sequences by ΔNp63 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 ΔNp63 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 ΔNp63 and p53 in regulating RUNX1 transcription factor expression for proper regulation of interfollicular epidermal homeostasis.
Highlights
P63 belongs to the p53/p63/p73 family of transcription factors (TFs) that share a conserved DNA-binding domain and similar
The present study shows for the first time that RUNX1 is expressed in human interfollicular epidermis, while being restricted to hair follicles in mouse skin.[18]
These results are in line with the strong DNp63 expression in human interfollicular epidermis, shown as a direct transcriptional regulator of RUNX1.9–11 We have demonstrated that RUNX1 is tightly regulated by a complex mechanism involving DNp63 and p53, and control cell proliferation and onset of differentiation
Summary
P63 belongs to the p53/p63/p73 family of transcription factors (TFs) that share a conserved DNA-binding domain and similar. RUNX family genes share a region, the Runt domain, which, with its partner subunit core-binding factor beta (CBFb), is responsible for specific DNA binding and heterodimerization and activates or represses transcription through the recruitment of various coactivators and corepressors depending on the cellular context.[12] The RUNX genes have a complex role in cancer, acting as either tumor suppressors or dominant oncogenes.[13] RUNX1 is a master regulator in the development, growth and differentiation of hematopoietic,[14] muscular[15] and nerve cells.[16] In mouse skin, RUNX1 expression was found in hair follicles, and its specific disruption in mouse epidermal cells impaired hair follicle homeostasis and long-term differentiation.[17,18,19] In human skin, RUNX1 is highly expressed in hair follicles and involved in KAP5 regulation, a keratin-associated protein expressed in the cuticle layer of anagen hair follicles.[20]
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