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Gadd45a  -  growth arrest and DNA-damage-inducible 45...

Mus musculus

Synonyms: AA545191, DDIT-1, DNA damage-inducible transcript 1 protein, Ddit1, GADD45, ...
 
 
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Disease relevance of Gadd45a

 

High impact information on Gadd45a

  • Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability [5].
  • Genomic instability in Gadd45a-deficient mice [5].
  • Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy [5].
  • We find that Gadd45a is a negative regulator of T cell proliferation because, compared to wild-type cells, Gadd45a(-/-) T cells have a lower threshold of activation and proliferate to a greater extent following primary T cell receptor stimulation [6].
  • Here we show that the lack of both Gadd45a and p21 dramatically accelerates the development of autoimmunity observed in each individual single-gene disruption mutant, demonstrating that these genes play nonredundant roles in the immune response [6].
 

Chemical compound and disease context of Gadd45a

  • Gadd45 and Gadd153 messenger RNA levels are increased during hypoxia and after exposure of cells to agents which elevate the levels of the glucose-regulated proteins [7].
 

Biological context of Gadd45a

 

Anatomical context of Gadd45a

  • Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure [12].
  • It was recently shown that mouse embryonic fibroblast cells carrying a targeted deletion of exon 11 of Brca1 (Brca1(Delta11/Delta11)) or a Gadd45A-null mutation (Gadd45a(-/-)) suffer centrosome amplification [12].
  • The inability of Gadd45a-null keratinocytes to suppress beta-catenin may contribute to the resulting observation of increased MMP expression and activity along with significantly faster keratinocyte migration in Matrigel in vitro and accelerated wound closure in vivo [11].
  • Moreover, using RKO lung carcinoma cell lines, which express antisense Gadd45 RNA, data has been obtained, which indicates that all three Gadd45 proteins are likely to cooperate in activation of S and G2/M checkpoints following exposure of cells to UV irradiation [13].
  • We conclude that increased tolerance of airway and type II epithelial cells to hyperoxia is not attributed solely to expression of Gadd45a [3].
 

Associations of Gadd45a with chemical compounds

 

Regulatory relationships of Gadd45a

  • Along with the findings presented above, inducible expression of Gadd45a enhanced p53 accumulation after cell exposure to UVB [18].
  • These results support the hypothesis that Gadd45 enhances NER by negatively regulating basal p21 expression in keratinocytes [19].
  • However, as this suggestion relied on in vitro experiments and ectopic overexpression of Gadd45 protein, we examined whether physiological levels of Gadd45 that are induced following exposure to DNA damaging agents and stress can lead to JNK induction [20].
 

Other interactions of Gadd45a

  • The region of interaction was mapped to amino acids 71 to 96, and the central portion (amino acids 71 to 124) of Gadd45a was required for p38 MAPK activation in the presence of H-ras [8].
  • Herein we identify Gadd45a as an important negative regulator of two oncogenes commonly over-expressed in epithelial tumors: the p53 homologue DeltaNp63alpha and beta-catenin [11].
  • Gadd45a deletion allows another form of genomic instability, gene amplification, when p21 (Cdkn1a gene product) is deleted also [15].
  • We demonstrate that lack of Gadd45a not only prevents DeltaNp63alpha suppression and GSK3beta dephosphorylation but also prevents free cytoplasmic beta-catenin degradation after UV irradiation [11].
  • Atm-, p53-, and Gadd45a-deficient mice show an increased frequency of homologous recombination at different stages during development [9].
 

Analytical, diagnostic and therapeutic context of Gadd45a

  • Increased levels of Gadd45a transcript and protein are seen after treatment of cells with ionizing radiation as well as many other agents and treatments that damage DNA [21].
  • These results establish an unambiguous role for the GADD45 family as an essential mediator of cell survival in cancer cells with implications for cancer chemotherapy and novel drug discovery [22].
  • These results show that Gadd45 isoforms function in common but also in distinct pathways during hyperosmolality and that their increased abundance contributes to the low mitotic index and protection of genomic integrity in cells of the mammalian renal inner medulla [23].
  • Using transient overexpression of ectopic Gadd45 proteins and simultaneous analysis of transfected versus non-transfected cells by laser-scanning cytometry, we were able to measure the effects of Gadd45 super-induction during hyperosmolality on G(2)/M arrest and apoptosis [23].
  • Immunoprecipitation of Gadd45 from mammalian cells reveals that it is tightly associated with a protein which reacts with antibodies to the cyclin dependent kinase inhibitor p21Cip1 [24].

References

  1. Transcriptional up-regulation of Gadd45a in Patched-associated medulloblastoma. Kappler, R., Hess, I., Schlegel, J., Hahn, H. Int. J. Oncol. (2004) [Pubmed]
  2. Gadd45a acts as a modifier locus for lymphoblastic lymphoma. Hollander, M.C., Patterson, A.D., Salvador, J.M., Anver, M.R., Hunger, S.P., Fornace, A.J. Leukemia (2005) [Pubmed]
  3. Loss of Gadd45a does not modify the pulmonary response to oxidative stress. Roper, J.M., Gehen, S.C., Staversky, R.J., Hollander, M.C., Fornace, A.J., O'Reilly, M.A. Am. J. Physiol. Lung Cell Mol. Physiol. (2005) [Pubmed]
  4. Gadd45a Suppresses Ras-Driven Mammary Tumorigenesis by Activation of c-Jun NH2-Terminal Kinase and p38 Stress Signaling Resulting in Apoptosis and Senescence. Tront, J.S., Hoffman, B., Liebermann, D.A. Cancer Res. (2006) [Pubmed]
  5. Genomic instability in Gadd45a-deficient mice. Hollander, M.C., Sheikh, M.S., Bulavin, D.V., Lundgren, K., Augeri-Henmueller, L., Shehee, R., Molinaro, T.A., Kim, K.E., Tolosa, E., Ashwell, J.D., Rosenberg, M.P., Zhan, Q., Fernández-Salguero, P.M., Morgan, W.F., Deng, C.X., Fornace, A.J. Nat. Genet. (1999) [Pubmed]
  6. Mice lacking the p53-effector gene Gadd45a develop a lupus-like syndrome. Salvador, J.M., Hollander, M.C., Nguyen, A.T., Kopp, J.B., Barisoni, L., Moore, J.K., Ashwell, J.D., Fornace, A.J. Immunity (2002) [Pubmed]
  7. Gadd45 and Gadd153 messenger RNA levels are increased during hypoxia and after exposure of cells to agents which elevate the levels of the glucose-regulated proteins. Price, B.D., Calderwood, S.K. Cancer Res. (1992) [Pubmed]
  8. Loss of oncogenic H-ras-induced cell cycle arrest and p38 mitogen-activated protein kinase activation by disruption of Gadd45a. Bulavin, D.V., Kovalsky, O., Hollander, M.C., Fornace, A.J. Mol. Cell. Biol. (2003) [Pubmed]
  9. Atm-, p53-, and Gadd45a-deficient mice show an increased frequency of homologous recombination at different stages during development. Bishop, A.J., Hollander, M.C., Kosaras, B., Sidman, R.L., Fornace, A.J., Schiestl, R.H. Cancer Res. (2003) [Pubmed]
  10. Gadd45a and Gadd45b protect hematopoietic cells from UV-induced apoptosis via distinct signaling pathways, including p38 activation and JNK inhibition. Gupta, M., Gupta, S.K., Hoffman, B., Liebermann, D.A. J. Biol. Chem. (2006) [Pubmed]
  11. Gadd45a regulates matrix metalloproteinases by suppressing DeltaNp63alpha and beta-catenin via p38 MAP kinase and APC complex activation. Hildesheim, J., Belova, G.I., Tyner, S.D., Zhou, X., Vardanian, L., Fornace, A.J. Oncogene (2004) [Pubmed]
  12. Genetic interactions between Brca1 and Gadd45a in centrosome duplication, genetic stability, and neural tube closure. Wang, X., Wang, R.H., Li, W., Xu, X., Hollander, M.C., Fornace, A.J., Deng, C.X. J. Biol. Chem. (2004) [Pubmed]
  13. GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. Vairapandi, M., Balliet, A.G., Hoffman, B., Liebermann, D.A. J. Cell. Physiol. (2002) [Pubmed]
  14. Effects of expression of p53 and Gadd45 on osmotic tolerance of renal inner medullary cells. Cai, Q., Dmitrieva, N.I., Ferraris, J.D., Michea, L.F., Salvador, J.M., Hollander, M.C., Fornace, A.J., Fenton, R.A., Burg, M.B. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  15. Genomic instability in Gadd45a-/- cells is coupled with S-phase checkpoint defects. Hollander, M.C., Philburn, R.T., Patterson, A.D., Wyatt, M.A., Fornace, A.J. Cell Cycle (2005) [Pubmed]
  16. CR6-interacting factor 1 interacts with Gadd45 family proteins and modulates the cell cycle. Chung, H.K., Yi, Y.W., Jung, N.C., Kim, D., Suh, J.M., Kim, H., Park, K.C., Song, J.H., Kim, D.W., Hwang, E.S., Yoon, S.H., Bae, Y.S., Kim, J.M., Bae, I., Shong, M. J. Biol. Chem. (2003) [Pubmed]
  17. Three GADD45 isoforms contribute to hypertonic stress phenotype of murine renal inner medullary cells. Chakravarty, D., Cai, Q., Ferraris, J.D., Michea, L., Burg, M.B., Kültz, D. Am. J. Physiol. Renal Physiol. (2002) [Pubmed]
  18. Gadd45a contributes to p53 stabilization in response to DNA damage. Jin, S., Mazzacurati, L., Zhu, X., Tong, T., Song, Y., Shujuan, S., Petrik, K.L., Rajasekaran, B., Wu, M., Zhan, Q. Oncogene (2003) [Pubmed]
  19. Loss of p21WAF1/Cip1 in Gadd45-deficient keratinocytes restores DNA repair capacity. Maeda, T., Espino, R.A., Chomey, E.G., Luong, L., Bano, A., Meakins, D., Tron, V.A. Carcinogenesis (2005) [Pubmed]
  20. Stress-induced JNK activation is independent of Gadd45 induction. Shaulian, E., Karin, M. J. Biol. Chem. (1999) [Pubmed]
  21. Dimethylbenzanthracene carcinogenesis in Gadd45a-null mice is associated with decreased DNA repair and increased mutation frequency. Hollander, M.C., Kovalsky, O., Salvador, J.M., Kim, K.E., Patterson, A.D., Haines, D.C., Fornace, A.J. Cancer Res. (2001) [Pubmed]
  22. NF-kappa B-mediated repression of growth arrest- and DNA-damage-inducible proteins 45alpha and gamma is essential for cancer cell survival. Zerbini, L.F., Wang, Y., Czibere, A., Correa, R.G., Cho, J.Y., Ijiri, K., Wei, W., Joseph, M., Gu, X., Grall, F., Goldring, M.B., Zhou, J.R., Libermann, T.A., Zhou, J.R. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  23. Gadd45 proteins induce G2/M arrest and modulate apoptosis in kidney cells exposed to hyperosmotic stress. Mak, S.K., Kültz, D. J. Biol. Chem. (2004) [Pubmed]
  24. Gadd45 is a nuclear cell cycle regulated protein which interacts with p21Cip1. Kearsey, J.M., Coates, P.J., Prescott, A.R., Warbrick, E., Hall, P.A. Oncogene (1995) [Pubmed]
 
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