The E2F4/p130 repressor complex cooperates with oncogenic deltaNp73alpha to inhibit gene expression in human papillomavirus 38 E6/E7-transformed keratinocytes and in cancer cells

Published: 13 February 2023| Version 1 | DOI: 10.17632/rpw2j5fzj4.1
Katia Zanier


Tumor suppressor p53 and its related proteins, p63 and p73, can be synthesized as multiple isoforms lacking part of the N- or C-terminal regions. Specifically, high expression of the deltaNp73alpha (DNp73a) isoform is notoriously associated with various human malignancies characterized by poor prognosis. This isoform is also accumulated by oncogenic viruses such as Epstein–Barr virus (EBV), as well as genus beta human papillomaviruses (HPV) that appear to be involved in carcinogenesis. To gain additional insight into DNp73a mechanisms, we have performed proteomics analyses using human keratinocytes transformed by the E6 and E7 proteins of the beta-HPV type 38 virus as an experimental model (38HK). We find that DNp73a associates with the E2F4/p130 repressor complex through a direct interaction with E2F4. This interaction is favored by the N-terminal truncation of p73 characteristic of DNp73 isoforms. Moreover, it is independent of the C-terminal splicing status, suggesting that it could represent a general feature of DNp73 isoforms. We show that the DNp73a-E2F4/p130 complex inhibits the expression of specific genes, including genes encoding for negative regulators of proliferation, both in 38HK and in HPV-negative cancer-derived cell lines. Such genes are not inhibited by E2F4/p130 in primary keratinocytes lacking DNp73a, indicating that the interaction with DNp73a rewires the E2F4 transcriptional program. In conclusion, we have identified and characterized a novel transcriptional regulatory complex with potential implications in oncogenesis.



Centre National de la Recherche Scientifique


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