The transcription factor E2F1 plays a pivotal role in the control of cell proliferation and apoptosis. Recently we uncovered a novel pocket proteins-independent pathway involving PI3K/Akt and a BRCT domain-containing protein TopBP1 in the control of E2F1 Our preliminary data further demonstrate E2F can be regulated by another BRCT domain-containing protein, MCPH1/BRIT1. The pRb family members have long been considered to be the major regulators for E2F. TopBP1 and MCPH1 appear to be a new class of E2F regulators. They both contain multiple BRCT motifs and interact with the N- terminus of E2F1 through their BRCT motifs. TopBP1 is a negative regulator, whereas, MCPH1 is a positive regulator of E2F1 target genes in checkpoint/repair and apoptosis. Both proteins are also directly involved in DNA damage checkpoint activation. In this proposal, we aim to characterize the functions and mechanisms of these novel regulations governing E2F1 protein activity and stability. First, We will elucidate the mechanism by which growth factor signalings control E2F1 through TopBP1. Second, We will determine how MCPH1 regulates E2F1. How TopBP1 and MCPH1 respond to environmental milieu and regulate E2F1 activity will also be investigated. Lastly, we will investigate how E2F1 protein is induced in response to ATM phosphorylation. Upon completion of this project, we will elucidate how the proliferative and pro-apoptotic activities of E2F1 are differentially regulated. Understanding the control of E2F1 activity and stability in growth and DNA damage may provide novel approaches in harness E2F1 pro-apoptotic activity to enhance chemosensitivity.

Public Health Relevance

Proper balance between proliferation and cell death is essential for normal growth. Recent studies have established a role for E2F1 in this control, especially upon DNA damage. During our last grant period, we discovered a novel class of E2F1 regulators. We will elucidate the mechanisms of regulation and the implications to clinical application in enhancing E2F1-induced cell killing in cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100857-09
Application #
8225244
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Pelroy, Richard
Project Start
2003-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$306,630
Indirect Cost
$106,871
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
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
Xiao, Yang; Lin, Vivian Y; Ke, Shi et al. (2014) 14-3-3τ promotes breast cancer invasion and metastasis by inhibiting RhoGDIα. 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
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
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
Budhavarapu, Varija N; White, Erin D; Mahanic, Christina S et al. (2012) Regulation of E2F1 by APC/C Cdh1 via K11 linkage-specific ubiquitin chain formation. Cell Cycle 11:2030-8
Klionsky, Daniel J (author list too long to display - see original citation for additional authors) (2012) Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8:445-544

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