Abstract

The overall goal of this project is to study the regulation of E2F1 stability and specific role of E2F1 for DNA damage. While the function of E2F in cell cycle progression is well established, our recent works demonstrate an important role of E2F1 for DNA damage response. ATM/ATR can phosphorylate E2F1 and lead to stabilization of E2F1. The induction of E2F1 is required for DNA damage-induced apoptosis. Thus E2F1 appears to participate in the DNA damage checkpoint control, which is often lost in human cancers. To further understand how E2F1 participates in the checkpoint control, we identified three proteins that interact with E2F1 and may regulate E2F1 during DNA damage. We propose to study how these proteins regulate E2F1.
Aim 1 : Explore the role of TopBP1/E2F interaction in transcription and replication control. To test the hypothesis: Regulation of E2F1 by TopBP1 is required for proper DNA damage response.
Aim 2 : Test the role of 14-3-3 in the regulation of E2F stability and activity. To test the hypothesis: Binding of 14-3-3 to E2F1 induces the stability and activity of E2F1.
Aim 3 : Test the role of hHYD for E2F degradation. To test the hypothesis: hHYD targets E2F1 for ubiquitination and binding of 14-3-3 protects E2F1 from degradation. We will employ biochemical, genetic and fluorescent microscope methodology as well as DNA microarray analysis to address these questions. The knowledge obtained from this study will be important in the understanding of how normal cells respond to genotoxic stress. A loss of the proper response may lead to tumor development.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100857-05
Application #
7368103
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Pelroy, Richard
Project Start
2004-04-15
Project End
2009-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$278,662
Indirect Cost

  Institution

Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294

  Publications

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

Showing the most recent 10 out of 22 publications