Year: 2008
Type: dissertation
Abstract: The p53 paralogues p73, p63 and their respective truncated isoforms have\nbeen shown to be critical regulators of developmental and differentiation\nprocesses. Indeed, both p73 and p63 deficient mice exhibit severe\ndevelopmental defects. Here, we show that the S100A2 gene, whose\ntranscript and protein are induced during keratinocyte differentiation of\nHaCaT cells, is a direct transcriptional target of p73β and ΔNp63α and is\nrequired for proper keratinocyte differentiation. Transactivation assays\nreveal that p73β and ΔNp63α exert opposite transcriptional effects on the\nS100A2 gene. While ΔNp63α is found in vivo onto S100A2 regulatory\nregions predominantly in proliferating cells, p73β is recruited in\ndifferentiating cells. Silencing of p73 impairs the induction of S100A2\nduring the differentiation of HaCaT cells. Moreover, silencing of p73 or\nS100A2 impairs the proper expression of keratinocyte differentiation\nmarkers. Of note, p53 family members do not trigger S100A2 gene\nexpression in response to apoptotic doses of cisplatin and doxorubicin.\nThe p53 family is also known to be involved in the transcriptional control of\ngrowth arrest and apoptosis. Despite the recent identification of specific p73-\ntarget genes by genome-wide expression profile techniques, p73-mediated\napoptosis occurs mostly through the activation of a set of genes that were\noriginally found to be activated by p53. This suggests that promoter\nselectivity by both p53 and p73 might be the result of biochemical events\nsuch as post-translational modifications and specific protein-protein\ninteractions.\nThe transcriptional coactivator Yes-associated protein (YAP) has been\ndemonstrated to interact with and to enhance p73-dependent apoptosis in\nresponse to DNA damage. Here we show the existence of specific target\ngenes whose transcriptional activation during the apoptotic response requires\nboth p73 and YAP. In particular p73 and YAP are concomitantly recruited\nonto the regulatory regions of the promyelocytic leukemia gene (PML); an\nessential event for PML induction after cisplatin treatment. Moreover,\nsequestring YAP into the cytoplasm by a constitutively active mutant of\nAKT leads to a reduction of p300 recruitment onto the PML regulatory\nregions which correlates with a reduction in histone acetylation and a\nreduction in PML expression. Finally, we show that PML binds to YAP and\nplays a role in the regulation of YAP half-life, preventing its ubiquitinylation\nand subsequent degradation.
Author: Eleonora Lapi
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2341100407