Abstract
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.
Highlights
RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination
We show that ZNF768 depletion impairs proliferation and rapidly induces cellular senescence by modulating the expression of key cell cycle effectors and p53 target genes
Cancer genomics and immunohistochemical analyses revealed that ZNF768 is frequently amplified and/or overexpressed in various human malignancies, suggesting that ZNF768 could contribute to the bypass of cellular senescence and to the promotion of oncogene-induced transformation
Summary
RAS proteins are GTPases that lie upstream of a signaling network impacting cell fate determination. RAS proteins (HRAS, NRAS, and KRAS) are small GTPases that lie upstream of a broad signaling network controlling proliferation These proteins are often mutated and hyperactive in tumor cells[1]. RAS signaling is important to support proliferation, unrestrained RAS activation in primary mammalian cells typically triggers a cascade of molecular and cellular events leading to cellular senescence, a state of permanent cell cycle arrest in which cells remain metabolically active[8] This process, termed oncogene-induced senescence, has emerged as an important cancer-protective response to oncogenic events, serving to eliminate early neoplastic cells[9,10,11,12]. Cancer genomics and immunohistochemical analyses revealed that ZNF768 is frequently amplified and/or overexpressed in various human malignancies, suggesting that ZNF768 could contribute to the bypass of cellular senescence and to the promotion of oncogene-induced transformation. We identify ZNF768 as a target of RAS linking growth factor signaling to the control of cell proliferation
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