Gadd 45 genes sensors of stress and tumor modulators

GADD45基因(a，b，g)是压力感受器，调节哺乳动物细胞对 基因毒性/生理应激，并调节肿瘤的形成。GADD45蛋白与其他蛋白相互作用 参与应激反应的蛋白，包括增殖细胞核抗原、p21、CDc2/CylinB1、MEKK4和p38激酶。至 GADD45蛋白的功能在多大程度上重叠？应激刺激的性质如何决定GADD45 细胞存活或死亡的信号功能尚不清楚。需要检验的假设是， 应激的性质/大小决定了GADD45蛋白将与哪些伙伴相关联以向细胞发出信号 生存还是细胞死亡。在低应激条件下，GADD45蛋白可能与p21、cdc2/cyClinB1& 增殖细胞核抗原激活细胞周期停滞和DNA修复，最终促进细胞存活，而在 对高应激的反应，包括细胞老化和激活的癌基因，GADD45蛋白可能相互作用 应激蛋白激酶(MEKK4、p38、JNK)促进细胞凋亡或衰老。据推测，压力 GADD45蛋白的传感功能在调节肿瘤的形成中发挥作用。缺乏一只的小鼠 或更多与特定伴侣结合不足的GADD45基因和GADD45突变蛋白 产生来检验这一假设。目标1将评估GADD45和互动伙伴在 细胞对不同剂量的基因毒性应激的反应。GADD45缺陷对细胞的影响 暴露于GADD45 KO和WT细胞后的细胞周期停滞、存活或凋亡 将测试低/高水平的基因毒性应激。此外，GADD45/伙伴蛋白相互作用的作用 将通过测试转导的wt/突变体GADD45基因拯救wt表型的能力来探索。 目标2将评估GADD45及其伙伴在MEF对生理/致癌反应中的作用 压力。Gadd45a-/-和Gadd45G-/-MEF被发现逃避复制和癌基因介导的 衰老，而gadd45b-/-MEF失去活力。还发现了Gadd45a-/-&gadd45g-/-MEF 对ras转化敏感，而gadd45a/gadd45g双KO MEF敏感 用于RAS或MYC的转换。GADD45和互动伙伴在衰老中扮演的角色， 本课程将探讨生存和对转变的敏感性。目标3将评估GADD45的功能 基因作为肿瘤发展的调节器。易患乳腺癌的MMTV-ras和MMTV-myc小鼠 为gadd45a生成了wt或空。Gadd45a缺乏加速MMTV-ras肿瘤的形成， 然而，MMTV-myc乳腺癌的发生被延缓，表明gadd45a具有肿瘤功能。 启动子/抑制子依赖于癌基因。实验的目的是评估这种作用 GADD45基因的应激反应功能在差异调控ras和myc驱动的乳房中的作用 肿瘤发生学。这项研究应该提供对更好地 了解压力感应器在肿瘤发生中的作用，以及肿瘤治疗中的治疗抵抗 可以出现，也可以被废除。GADD45基因(a，b，g)是重要的应激感受器，调节哺乳动物细胞对 基因毒性/生理应激，并调节癌症的发展。GADD45蛋白与其他蛋白相互作用 与应激反应有关的蛋白质。需要检验的假设是， 应激决定GADD45蛋白将与哪些伙伴相关联，以传递细胞生存或死亡的信号 缺乏一个或多个GADD45基因和GADD45突变蛋白与特定结合缺陷的小鼠 为了检验这一假设，研究人员产生了合作伙伴。目标1将评估GADD45和互动的作用 参与细胞对不同剂量的基因毒性应激的反应。目标2将评估GADD45的作用 &参与细胞对生理和致癌压力的反应。目标3将评估 GADD45基因作为乳腺癌发生的调节因子。这项研究应该会提供信息， 对于更好地理解应力传感器在肿瘤发生中的作用以及如何 癌症治疗中的治疗抵抗可能会出现并被废除。

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.