p53 dynamics vary between tissues and are linked with radiation sensitivity

Jacob Stewart-Ornstein, Yoshiko Iwamoto, Miles A. Miller, Mark A. Prytyskach, Stephane Ferretti, Philipp Holzer, Joerg Kallen, Pascal Furet, Ashwini Jambhekar, William C. Forrester, Ralph Weissleder () and Galit Lahav ()
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Jacob Stewart-Ornstein: Blavatnik Institute at Harvard Medical School
Yoshiko Iwamoto: Massachusetts General Hospital
Miles A. Miller: Massachusetts General Hospital
Mark A. Prytyskach: Massachusetts General Hospital
Stephane Ferretti: Novartis Institutes for Biomedical Research
Philipp Holzer: Novartis Institutes for Biomedical Research
Joerg Kallen: Novartis Institutes for Biomedical Research
Pascal Furet: Novartis Institutes for Biomedical Research
Ashwini Jambhekar: Blavatnik Institute at Harvard Medical School
William C. Forrester: Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research
Ralph Weissleder: Blavatnik Institute at Harvard Medical School
Galit Lahav: Blavatnik Institute at Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract Radiation sensitivity varies greatly between tissues. The transcription factor p53 mediates the response to radiation; however, the abundance of p53 protein does not correlate well with the extent of radiosensitivity across tissues. Given recent studies showing that the temporal dynamics of p53 influence the fate of cultured cells in response to irradiation, we set out to determine the dynamic behavior of p53 and its impact on radiation sensitivity in vivo. We find that radiosensitive tissues show prolonged p53 signaling after radiation, while more resistant tissues show transient p53 activation. Sustaining p53 using a small molecule (NMI801) that inhibits Mdm2, a negative regulator of p53, reduced viability in cell culture and suppressed tumor growth. Our work proposes a mechanism for the control of radiation sensitivity and suggests tools to alter the dynamics of p53 to enhance tumor clearance. Similar approaches can be used to enhance killing of cancer cells or reduce toxicity in normal tissues following genotoxic therapies.

Date: 2021
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DOI: 10.1038/s41467-021-21145-z

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