Editors' ChoiceCancer

p21: One protein to rule cell fate

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Science Translational Medicine  03 Jul 2019:
Vol. 11, Issue 499, eaay3568
DOI: 10.1126/scitranslmed.aay3568

Abstract

Early p21 expression controls cells’ proliferation/senescence fate after chemotherapy.

When cancer is being treated with chemotherapy, surviving cells can acquire a proliferative or senescent phenotype. The cyclin-dependent kinase inhibitor p21 is usually considered to be a key promoter of the latter.

Hsu and colleagues elegantly demonstrated in vitro that initial expression of p21 after chemotherapy exposure controls downstream cell fate after DNA damage induced by 1-day treatment with doxorubicin. They used a CRISPR-based p21 fluorescence tagging technique, a cell-cycle phase detector, several probes (for DNA damage and cell proliferation), and imaging analyses to track p21 dynamics and phenotype over time at single-cell level. By modulating the expression of p21, the authors identified a causal role for early p21 expression during the drug pulse in determining individual cell-fate decisions to undergo proliferation or senescence by day 5. Unexpectedly, most cells that endured high amounts of DNA damage in S and G2 phases had low expression of p21 at early time points, but it increased over time, resulting in senescence. In contrast, moderate cellular DNA damage, observed in G1 phase, caused an unstable intermediate p21 state in which cells could evolve to p21low and adopt a proliferative phenotype or progress to p21high and become senescent. The authors found that a p21high state during G1 was mostly caused by the activation of ataxia-telangiectasia mutated protein (ATM) signaling, whereas a p21low state in S/G2 was mainly due to repression of p21 by checkpoint kinase 1 (CHK1) signaling and proteasomal degradation. p53 is a direct transcriptional activator of p21, and Myc suppresses this activation, yet the authors demonstrated using siRNA strategies that these proteins cannot directly justify the observed p21 dynamics. Finally, Hsu and colleagues described different pharmacological strategies to reduce the lasting proliferative and senescent subpopulations after chemotherapy, by inhibiting ATM/CHK1 and anti-apoptotic proteins, respectively.

This study suggests that targeting the G1/S checkpoint can help avoid proliferation of cancer cells that survive chemotherapy. Several unanswered questions remain, such as the role of p21 phosphorylation in cell-fate decisions, the effects of current p53-targeting strategies on long-term proliferation potential of cancer cells, or the roles of other proteins that regulate cell cycle and senescence. Nonetheless, this study could improve cancer treatment by helping to identify combinations of drugs that avoid tumor relapse due to cells’ return to proliferative state.

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