Accumulating evidence indicate that perturbations in the regulated expression of protein kinases or their associated signaling pathways can lead to malignant transformation. We have recently identified a cDNA clone as a p53-target gene using differential screening, which was also responsive to DNA damage. This clone, DDR1/Cak1/TrkE/RTK6, encodes a novel family member of the receptor tyrosine kinases. Although the biological role of DDR1 has not yet been defined, transactivation of the DDR1 gene by p53 and DNA damage and its potential function as a receptor tyrosine kinase are intriguing. Our preliminary data suggest that, unlike other p53 target genes that function as either cell cycle inhibitors or apoptosispromoters, DDR1 kinase promotes cell survival by counteracting p53-mediated cell death/apoptosis. Moreover, DDR1 expression induced levels of p53, p21 and Arf/p19 in wt-p53 containing cells but not in p53-null or mutant cells. The findings suggest that DDR1 may function through a positive feed back loop of the p53-DDR1-Ras/Raf/MAPK-p53 module in the regulation of p53. Our working hypothesis is that p53 activates MAPK and/or AKT through DDR1 up-regulation to promote cell survival, and that inhibition of DDR1 function enhances the cell killing effects of p53 induction. DDR1 may be part of a cellular regulatory switch that dictates the cellular decision to undergo either arrest or apoptosis. In this proposal, we will address how these cellular outcomes are governed, and whether or not DDR1-mediated MAPK/ERK activation participates in and abrogates the p53/DNA damage-induced apoptosis. Better understanding of the role(s) of DDR1 should offer a unique opportunity to study a novel mechanism of p53-mediated tumor suppression and to develop novel approaches for targeting human cancers with normal p53 function, involving the inhibition of DDR1 receptor signaling.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097216-04
Application #
6909083
Study Section
Special Emphasis Panel (ZRG1-PTHB (01))
Program Officer
Blair, Donald G
Project Start
2003-07-01
Project End
2008-04-30
Budget Start
2005-07-21
Budget End
2006-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$311,500
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Zhu, Zehua; Todorova, Kristina; Lee, Kevin K et al. (2014) Small GTPase RhoE/Rnd3 is a critical regulator of Notch1 signaling. Cancer Res 74:2082-93
Kim, Hyung-Gu; Hwang, So-Young; Aaronson, Stuart A et al. (2011) DDR1 receptor tyrosine kinase promotes prosurvival pathway through Notch1 activation. J Biol Chem 286:17672-81
Hwang, Sun Ok; Boswell, Sarah A; Seo, Jeong-Sun et al. (2008) Novel oxidative stress-responsive gene ERS25 functions as a regulator of the heat-shock and cell death response. J Biol Chem 283:13063-9
Munoz-Fontela, Cesar; Macip, Salvador; Martinez-Sobrido, Luis et al. (2008) Transcriptional role of p53 in interferon-mediated antiviral immunity. J Exp Med 205:1929-38
Das, Sanjeev; Boswell, Sarah A; Aaronson, Stuart A et al. (2008) P53 promoter selection: choosing between life and death. Cell Cycle 7:154-7
Boswell, Sarah A; Ongusaha, Pat P; Nghiem, Paul et al. (2007) The protective role of a small GTPase RhoE against UVB-induced DNA damage in keratinocytes. J Biol Chem 282:4850-8
Brown, Lauren; Ongusaha, Pat P; Kim, Hyung-Gu et al. (2007) CDIP, a novel pro-apoptotic gene, regulates TNFalpha-mediated apoptosis in a p53-dependent manner. EMBO J 26:3410-22
Das, Sanjeev; Raj, Lakshmi; Zhao, Bo et al. (2007) Hzf Determines cell survival upon genotoxic stress by modulating p53 transactivation. Cell 130:624-37
Lee, Junghee; Kosaras, Bela; Aleyasin, Hossein et al. (2006) Role of cyclooxygenase-2 induction by transcription factor Sp1 and Sp3 in neuronal oxidative and DNA damage response. FASEB J 20:2375-7
Ongusaha, Pat P; Kim, Hyung-Gu; Boswell, Sarah A et al. (2006) RhoE is a pro-survival p53 target gene that inhibits ROCK I-mediated apoptosis in response to genotoxic stress. Curr Biol 16:2466-72

Showing the most recent 10 out of 13 publications