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Regulation of Ferroptosis by the p53/CDK/Rb Axis.

Regulation of Ferroptosis by the p53/CDK/Rb Axis.
p53/CDK/Rb 轴对铁死亡的调节。
批准号:
10203213
负责人:
William R. Taylor
金额:
$45.15万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-06-01 至 2025-05-31

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中文摘要
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英文摘要
Project Summary/Abstract: Despite advances in treatment, the five-year survival rates for certain types of cancer are still low. For example, only ~20% of patients with metastatic breast cancer are alive at 5 years. Uncontrolled proliferation is a hallmark of cancer and is caused by multiple mutations in genes including cell cycle regulators. Central to the control of cell proliferation are the tumor suppressors p53 and RB along with CDKs that modulate RB function. In the course of designing and testing a new class of anticancer drugs, we found that p53, RB and CDK2 can dramatically modulate cell sensitivity to ferroptosis, an iron-dependent, ROS-mediated form of cell death characterized by catastrophic lipid peroxidation. We observed that elevated p53 enhances ferroptosis, while elevated CDK2 blocks the response. Deletion of RB proteins enhances ferroptosis while overexpression of E2F1 has no effect. The classical model of RB as a simple inhibitor of E2F1 cannot explain our observations. However, our results can be reconciled by recently described activity of phosphorylated RB. Thus, we hypothesize that phosphorylated forms of RB actively contribute to the establishment of an anti-ferroptotic state, potentially in an E2F-independent manner. Based on this model, both elevated p53 and RB deletion enhance ferroptosis by removing phosphorylated RB, while CDK2 blocks ferroptosis by generating phosphorylated RB. To test our hypothesis, we propose the following specific aims: AIM 1. The role of RB phosphorylation in ferroptosis. Cells lacking RB proteins will be reconstituted with mutants of RB that cannot be phosphorylated by CDKs. Cells will be exposed to small molecules to induce ferroptosis to determine sensitivity. We predict that non-phosphorylatable RB protein will fail to suppress ferroptosis unlike the wild-type protein. Additional experiments will map the sites of RB phosphorylation that modulate ferroptosis. AIM 2. Downstream targets of RB in the regulation of ferroptosis. The mechanism by which RB proteins regulate ferroptosis is unknown. We have carried out microarray transcriptional profiling and review of public databases to identify a panel of genes that may mediate the effects of RB on ferroptosis. We will test candidate genes by overexpression or knock-down using RNAi to determine effects on ferroptosis. AIM 3. Coordination of p53, CDKs and RB in the ferroptotic response. Both p53 and CDKs regulate a number of targets in addition to the RB family, yet all three components modulate ferroptosis. We propose to determine whether p53, CDKs and RB work in a single pathway to regulate ferroptosis or whether parallel pathways are also involved. These experiments will involve testing ferroptosis sensitivity in a number of mutant cell lines lacking these proteins. p53 is a member of a family that includes p63 and p73 proteins both of which have partially overlapping functions with p53. Virtually nothing is known about the involvement of p63 and p73 in ferroptosis. We will use RNAi and overexpression to test their role in this process. A better understanding of how ferroptosis is regulated will fill an important gap in knowledge in the biology of cell division and will help in design of more effective cancer treatments.
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Regulation of Ferroptosis by the p53/CDK/Rb Axis.
  • 批准号:
    10632830
  • 项目类别:
  • 资助金额:
    $1.29万
  • 财政年份:
    2021
  • 负责人:
    William R. Taylor
  • 依托单位:
Regulation of the Mitotic Checkpoint by Gsk3
  • 批准号:
    9305429
  • 项目类别:
  • 资助金额:
    $44.25万
  • 财政年份:
    2017
  • 负责人:
    William R. Taylor
  • 依托单位:
Regulation of Sororin by Cdk1-mediated Phosphorylation.
  • 批准号:
    8232810
  • 项目类别:
  • 资助金额:
    $29.1万
  • 财政年份:
    2012
  • 负责人:
    William R. Taylor
  • 依托单位:
Regulation of Borealin Function by Mitotic Phosphorylation
  • 批准号:
    7897208
  • 项目类别:
  • 资助金额:
    $8.36万
  • 财政年份:
    2009
  • 负责人:
    William R. Taylor
  • 依托单位:
海外基金