The E2F1 transcription factor is involved in many diverse functions, such as cell cycle progression, differentiation, DNA repair and apoptosis. There has been a lot of progress in the understanding of its role and regulation during DNA damage, including new regulators and posttranslational modification. One of its regulators, TopBP1, is also involved in checkpoint activation. However, it is not clear whether and how the functions of TopBP1 in E2F1 regulation and checkpoint activation are coordinated. We have now elucidated how these functions are switched via a PI(3)K/Akt-dependent mechanism. This regulatory mechanism often goes awry in cancer. We have developed a new strategy to rectify this abnormality in cancer. In this proposal, we aim to determine how E2F1 apoptosis is regulated by these events and test this new strategy to activate the E2F1-dependent apoptosis for cancer therapy. First, We will investigate a new mechanism of how TopBP1 switches its functions between the checkpoint activation and E2F1 regulation and how it is perturbed in cancer. Second, we will investigate how E2F1 is regulated by K63-linked ubiquitination. We will determine the E3 ligase(s) responsible for K63-linked E2F1 ubiquitination and investigate how a deubiquitinase regulates E2F1 activity. Lastly, we will develop new therapeutic strategies to activate E2F1-mediated apoptosis in cancer. Upon completion of this project, these new data will greatly advance our understanding of the molecular mechanism controlling both transcription and checkpoint, and how this basic mechanism is commonly de- regulated in cancer. Our new data will also provide extensive knowledge regarding how K63-linked ubiquitination regulates E2F1 activity through the critical regulators (E3 ligases and a deubiquitinase enzyme). Importantly, for the first time, we will be able to harness E2F1 activity for promoting apoptosis in cancer cells.

Public Health Relevance

Proper control of cell proliferation, cell death and DNA damage response is crucial for normal growth. The goal of this proposal is to elucidate the mechanisms for this regulation and to understand how this control mechanism is deranged in cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100857-15
Application #
9655296
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Pelroy, Richard
Project Start
2003-04-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
15
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Ho, Shiuh-Rong; Lin, Weei-Chin (2018) RNF144A sustains EGFR signaling to promote EGF-dependent cell proliferation. J Biol Chem 293:16307-16323
Liu, Kang; Lin, Fang-Tsyr; Graves, Joshua D et al. (2017) Mutant p53 perturbs DNA replication checkpoint control through TopBP1 and Treslin. Proc Natl Acad Sci U S A 114:E3766-E3775
Lin, Fang-Tsyr; Lin, Vivian Y; Lin, Victor Tg et al. (2016) TRIP6 antagonizes the recruitment of A20 and CYLD to TRAF6 to promote the LPA2 receptor-mediated TRAF6 activation. Cell Discov 2:
Mahanic, Christina S; Budhavarapu, Varija; Graves, Joshua D et al. (2015) Regulation of E2 promoter binding factor 1 (E2F1) transcriptional activity through a deubiquitinating enzyme, UCH37. J Biol Chem 290:26508-22
Ho, Shiuh-Rong; Lee, Yu-Ju; Lin, Weei-Chin (2015) Regulation of RNF144A E3 Ubiquitin Ligase Activity by Self-association through Its Transmembrane Domain. J Biol Chem 290:23026-38
Chowdhury, Pinki; Lin, Gregory E; Liu, Kang et al. (2014) Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy. Nat Commun 5:5476
Xiao, Yang; Lin, Vivian Y; Ke, Shi et al. (2014) 14-3-3? promotes breast cancer invasion and metastasis by inhibiting RhoGDI?. Mol Cell Biol 34:2635-49
Ho, Shiuh-Rong; Mahanic, Christina S; Lee, Yu-Ju et al. (2014) RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage. Proc Natl Acad Sci U S A 111:E2646-55
Liu, Kang; Graves, Joshua D; Scott, Jessica D et al. (2013) Akt switches TopBP1 function from checkpoint activation to transcriptional regulation through phosphoserine binding-mediated oligomerization. Mol Cell Biol 33:4685-700
Lin, Victor T G; Lin, Vivian Y; Lai, Yun-Ju et al. (2013) TRIP6 regulates p27 KIP1 to promote tumorigenesis. Mol Cell Biol 33:1394-409

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