Keratin 17 (K17) is a stress-responsive intermediate filament protein that is upregulated in chronic skin diseases and in several carcinomas. We previously showed that K17 is induced in epidermal kera Show more
Keratin 17 (K17) is a stress-responsive intermediate filament protein that is upregulated in chronic skin diseases and in several carcinomas. We previously showed that K17 is induced in epidermal keratinocytes following exposure to DNA-damaging agents, promoting keratinocyte survival and chemically induced papilloma formation in mouse skin. Molecularly, K17 is recruited to the nucleus, where it impacts nuclear architecture, gene expression, and the DNA damage response (DDR). Here, we report on efforts to delineate K17-dependent processes during DDR by focusing on its interacting partners. Using mass spectrometry, we identified a network of K17-interacting Rho GTPase signaling proteins, including Rac1 and its activator Dock7. Biochemically, we confirmed that Rac1 and K17 interact directly in vitro and in A431 tumor keratinocytes, both at baseline and after ionizing radiation. We show that Show less
RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incomple Show more
RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. How cells integrate RAS activity to balance proliferation and cellular senescence is still incompletely characterized. Here, we identify ZNF768 as a phosphoprotein destabilized upon RAS activation. We report that ZNF768 depletion impairs proliferation and induces senescence by modulating the expression of key cell cycle effectors and established p53 targets. ZNF768 levels decrease in response to replicative-, stress- and oncogene-induced senescence. Interestingly, ZNF768 overexpression contributes to bypass RAS-induced senescence by repressing the p53 pathway. Furthermore, we show that ZNF768 interacts with and represses p53 phosphorylation and activity. Cancer genomics and immunohistochemical analyses reveal that ZNF768 is often amplified and/or overexpressed in tumors, suggesting that cells could use ZNF768 to bypass senescence, sustain proliferation and promote malignant transformation. Thus, we identify ZNF768 as a protein linking oncogenic signaling to the control of cell fate decision and proliferation. Show less