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.
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