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Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression.

ABSTRACT: Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). Whereas the loss of K98 acetylation (p53K98R) alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation sites (p534KR: K98R+ 3KR[K117R+K161R+K162R]) completely abolish its ability to regulate metabolic targets, such as TIGAR and SLC7A11. Notably, in contrast to p533KR, p534KR is severely defective in suppressing tumor growth in mouse xenograft models. Moreover, p534KR is still capable of inducing the p53-Mdm2 feedback loop, but p53-dependent ferroptotic responses are markedly abrogated. Together, these data indicate the critical role of p53 acetylation in ferroptotic responses and its remaining tumor suppression activity.

SUBMITTER: Wang SJ

PROVIDER: S-EPMC5227654 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Acetylation Is Crucial for p53-Mediated Ferroptosis and Tumor Suppression.

Wang Shang-Jui SJ Li Dawei D Ou Yang Y Jiang Le L Chen Yue Y Zhao Yingming Y Gu Wei W

Cell reports 20161001 2

Although previous studies indicate that loss of p53-mediated cell cycle arrest, apoptosis, and senescence does not completely abrogate its tumor suppression function, it is unclear how the remaining activities of p53 are regulated. Here, we have identified an acetylation site at lysine K98 in mouse p53 (or K101 for human p53). Whereas the loss of K98 acetylation (p53<sup>K98R</sup>) alone has very modest effects on p53-mediated transactivation, simultaneous mutations at all four acetylation site ...[more]

PMID: 27705786

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