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Regulation of Ferroptosis by Transcription Factor E2F1 and RB.

ABSTRACT: Tumor suppressor RB binds to E2F family proteins and modulates cell cycle progression. Cyclin dependent kinases (CDK) regulate the interaction of RB/E2F by phosphorylating RB. Previously, we have revealed that CDK2, RB and E2F inhibit ferroptosis. Ferroptosis is a non-apoptotic, iron-dependent form of cell death characterized by toxic lipid peroxidation. Here we provide evidence that CDK2 suppresses ferroptosis through phosphorylation of RB. We approach this question by overexpressing WT-RB or a mutant RB that cannot be phosphorylated by CDKs (RBΔCDK) along with CDK2/cyclinE followed by analysis of ferroptosis. We also observed that E2F1 regulates of both pro and anti-ferroptotic proteins including ALOX5, MYC SLC7A11, ATF4, and GPX4 and finally renders a net inhibitory role in ferroptosis. Interestingly, we also found a cell type dependent compensatory effect of E2F3 upon E2F1 depletion. This compensatory effect resulted in no change of ferroptotic target genes after E2F1 knock down in an osteosarcoma cell line. Taken together, our study reveals that cancer cells protect themselves from ferroptosis through cell cycle regulatory proteins.

SUBMITTER: Kuganesan N

PROVIDER: S-EPMC9915776 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Regulation of Ferroptosis by Transcription Factor E2F1 and RB.

Kuganesan Nishanth N Dlamini Samkeliso S Tillekeratne Viranga Lm VL Taylor William R WR

Research square 20230130

Tumor suppressor RB binds to E2F family proteins and modulates cell cycle progression. Cyclin dependent kinases (CDK) regulate the interaction of RB/E2F by phosphorylating RB. Previously, we have revealed that CDK2, RB and E2F inhibit ferroptosis. Ferroptosis is a non-apoptotic, iron-dependent form of cell death characterized by toxic lipid peroxidation. Here we provide evidence that CDK2 suppresses ferroptosis through phosphorylation of RB. We approach this question by overexpressing WT-RB or a ...[more]

PMID: 36778475

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Project description:The E2F family of transcription factors plays an important role in the control of the cell cycle, cell proliferation, and differentiation, and their role in ovarian function is just emerging. Although some evidence suggests a possible role of E2F1 in ovarian follicular development, what regulates its production in ovarian cells is unknown. Objectives of this study were to determine whether: (i) E2F1 gene expression in granulosa cells (GCs) and theca cells (TCs) change with follicular development and (ii) E2F1 mRNA abundance in TC and GC is hormonally regulated. Using real-time PCR, E2F1 mRNA abundance in GC was 5.5-fold greater (P < 0.05) in small (SM; 1 to 5 mm) than large (LG; >8 mm) follicles, but in TC, E2F1 expression did not differ among follicle sizes. SM-follicle GC had 2.1-fold greater (P < 0.05) E2F1 mRNA than TC. In SM-follicle GC, FGF9 induced a 7.6-fold increase in E2F1 mRNA abundance; however, FGF9 did not affect (P > 0.10) abundance of E2F1 mRNA in LG-follicle TC or GC. Follicle-stimulating hormone (FSH) had no effect (P > 0.10) on E2F1 gene expression in SM- or LG-follicle GC. SM-follicle GC were concomitantly treated with insulin-like growth factor 1 (30 ng/mL), FSH (30 ng/mL), and either 0 or 30 ng/mL of FGF9 with or without 50 µM of an E2F inhibitor (E2Fi; HLM0064741); FGF9 alone increased (P < 0.05) GC numbers, whereas E2Fi alone decreased (P < 0.05) GC numbers, and concomitant treatment of E2Fi with FGF9 blocked (P < 0.05) this stimulatory effect of FGF9. Estradiol production was inhibited (P < 0.05) by FGF9 alone and concomitant treatment of E2Fi with FGF9 attenuated (P < 0.05) this inhibitory effect of FGF9. SM-follicle GC treated with E2Fi decreased (P < 0.05) E2F1 mRNA abundance by 70%. Collectively, our studies show that GC E2F1 mRNA is developmentally and hormonally regulated in cattle. Inhibition of E2F1 reduced FGF9-induced GC proliferation and attenuated FGF9-inhibited estradiol production, indicating that E2F1 may be involved in follicular development in cattle.

Dataset Information

Regulation of Ferroptosis by Transcription Factor E2F1 and RB.

Publications

Regulation of Ferroptosis by Transcription Factor E2F1 and RB.

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