Abstract
p53 is a well-established critical cell cycle regulator. By inducing transcription of the gene encoding p21, p53 inhibits cyclin-dependent kinase (CDK)-mediated phosphorylation of cell cycle inhibitor retinoblastoma (RB) proteins. Phosphorylation of RB releases E2F transcription factor proteins that transactivate cell cycle-promoting genes. Here, we sought to uncover the contribution of p53, p21, CDK, RB, and E2F to the regulation of ferroptosis, an oxidative form of cell death. Our studies have uncovered unexpected complexity in this regulation. First, we showed that elevated levels of p53 enhance ferroptosis in multiple inducible and isogenic systems. On the other hand, we found that p21 suppresses ferroptosis. Elevation of CDK activity also suppressed ferroptosis under conditions where p21 suppressed ferroptosis, suggesting that the impact of p21 must extend beyond CDK inhibition. Furthermore, we showed that overexpression of E2F suppresses ferroptosis in part via a p21-dependent mechanism, consistent with reports that this transcription factor can induce transcription of p21. Finally, deletion of RB genes enhanced ferroptosis. Taken together, these results show that signals affecting ferroptotic sensitivity emanate from multiple points within the p53 tumor suppressor pathway.
Highlights
Through an interconnected series of pathways, external growth factors, DNA damage, and other stresses regulate effector proteins that control progression through the cell cycle [1,2]
The p53 tumor suppressor controls a major pathway that coordinates the cellular response to DNA damage [3]. p53 induced in response to DNA damage upregulates the Journal Pre-proof transcription of p21, an inhibitor of cyclin-dependent kinases (CDKs) [4]
We show that p21, CDKs, RB, and E2F modulate sensitivity to ferroptosis but not in a manner that can be explained by operation of a linear pathway culminating in E2F activation that is well-documented in cell cycle research
Summary
Through an interconnected series of pathways, external growth factors, DNA damage, and other stresses regulate effector proteins that control progression through the cell cycle [1,2]. The p53 tumor suppressor controls a major pathway that coordinates the cellular response to DNA damage [3]. P53 induced in response to DNA damage upregulates the Journal Pre-proof transcription of p21, an inhibitor of cyclin-dependent kinases (CDKs) [4]. Since CDKs phosphorylate RB to modulate its activity, this p53/p21/CDK/RB pathway links DNA damage to cell cycle arrest by modulating RB phosphorylation. Phosphorylation of RB by CDKs reduces RB binding to E2F resulting in increased transcription of E2F targets encoding cell cycle proteins [2]. As cells pass through G1, CDK2 phosphorylates RB on up to 14 sites to release E2F for cell cycle entry [5,6] the effect of phosphorylation on RB depends on the exact phosphorylation state and the specific RB-regulated activity in question
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