Gadd45 genes (a, b, g) are stress sensors that modulate the response of mammalian cells to genotoxic/physiological stress, and modulate tumor formation. Gadd45 proteins interact with other proteins implicated in stress responses, 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 to be 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, ultimately promoting 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 either 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 that are wt or null for gadd45a were generated. Gadd45a deficiency accelerated MMTV-ras tumor formation, yet retarded MMTV-myc breast carcinogenisis, 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. This research should yield information that will be of great importance to better understand the role of stress sensors in tumorigenesis, and how treatment resistance in cancer therapy can arise and be abrogated. Gadd45 genes (a, b, g) are important stress sensors that modulate the response of mammalian cells to genotoxic/physiological stress, and modulate cancer development. Gadd45 proteins interact with other proteins implicated in stress responses. The hypothesis to be tested is that the nature/magnitude of stress dictates which partners Gadd45 proteins will associate with to signal cell survival or cell death 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.
Aim 2 will assess role of Gadd45 &partners in the response of cells to physiological &oncogenic stress.
Aim 3 will assess function of gadd45 genes as modulators of breast cancer development. This research should yield information that will be of great importance to better understand the role of stress sensors in tumorigenesis, and how treatment resistance in cancer therapy can arise and be abrogated.
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