Gadd45 genes (a, b, g) are stress sensors that modulate the response of cells to genotoxic/physiological stress, & modulate tumor formation. Gadd45 proteins interact with other stress response proteins, including PCNA, p21, Cdc2/CyclinB1, MEKK4 & p38 kinase. To what extent the functions of Gadd45 proteins overlap, & how the nature of stress stimuli dictate Gadd45 functions to signal cell survival or cell death is unclear. The hypothesis tested is that the nature/magnitude of stress dictates which partners Gadd45 proteins will associate with to signal cell survival or cell death. In response to low stress Gadd45 proteins may interact with p21, cdc2/cyclinB1 & PCNA to activate cell cycle arrest and DNA repair to promote cell survival, whereas in response to high stress, including cellular aging & activated oncogenes, Gadd45 proteins may interact with stress kinases (MEKK4, p38, JNK) to promote apoptosis or senescence. It is surmised that stress sensing functions of Gadd45 proteins play a role in modulating tumor formation. Mice deficient for one or more gadd45 genes & Gadd45 mutant proteins deficient in binding to particular partners were generated to test the hypothesis.
Aim 1 will assess the role of Gadd45 & interacting partners in the response of cells to varying doses of genotoxic stress. The effect of Gadd45 deficiencies on cell cycle arrest, survival or apoptosis in gadd45 KO & WT cells in vitro & in vivo, following exposure to low/high levels of genotoxic stress will be tested. Also, the role of Gadd45/partner protein interactions will be explored by testing the ability of transduced wt/mutant gadd45 genes to rescue wt phenotypes.
Aim 2 will assess role of Gadd45 & partners in the response of MEFs to physiological/oncogenic stress. Gadd45a-/- & gadd45g-/- MEFs were found to escape replicative & oncogene mediated senescence, whereas gadd45b-/- MEFs lose viability. Gadd45a-/- & gadd45g-/- MEFs were also found to be susceptible to ras transformation, whereas gadd45a/gadd45g double KO MEFs were susceptible for transformation by ras or myc. The role Gadd45 & interacting partners play in senescence, survival & susceptibility to transformation will be explored.
Aim 3 will assess function of gadd45 genes as modulators of tumor development. Breast cancer prone MMTV-ras & MMTV-myc mice wt or null for gadd45a were generated. Gadd45a deficiency accelerated MMTV-ras tumor formation, yet retarded MMTV-myc carcinogenesis, indicating that gadd45a functions as tumor promoter/suppressor depending on the oncogene. Experiments are targeted at assessing the role stress response functions of gadd45 genes play in differentially modulating ras/myc driven breast tumorigenesis. Data obtained will be of great importance to better understand the role of stress sensors in tumorigenesis, & how treatment resistance in cancer therapy can arise & be abrogated. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA122376-01A1
Application #
7259237
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Pelroy, Richard
Project Start
2007-05-01
Project End
2012-02-29
Budget Start
2007-05-01
Budget End
2008-02-29
Support Year
1
Fiscal Year
2007
Total Cost
$285,000
Indirect Cost
Name
Temple University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Tront, Jennifer S; Huang, Yajue; Fornace Jr, Albert J et al. (2010) Gadd45a functions as a promoter or suppressor of breast cancer dependent on the oncogenic stress. Cancer Res 70:9671-81
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Zumbrun, Steven D; Hoffman, Barbara; Liebermann, Dan A (2009) Distinct mechanisms are utilized to induce stress sensor gadd45b by different stress stimuli. J Cell Biochem 108:1220-31