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.
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.
|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:|
|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|
|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|
|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|
|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|
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