Gadd45a suppresses Ras-driven mammary tumorigenesis by activation of c-Jun NH2-terminal kinase and p38 stress signaling resulting in apoptosis and senescence.
The Gadd45 family of proteins is known to play a central role as cellular stress sensors that modulate the response of mammalian cells to stress inflicted by physiologic and environmental stressors. Gadd45a was shown to be a direct target to the p53 and BRCA1 tumor suppressor genes, whose loss of function is known to play a vital role in breast carcinogenesis; however, the role of Gadd45a in the suppression of breast cancer remains unclear. To address this issue, Gadd45a-deficient mice were crossed with breast cancer prone mouse mammary tumor virus-Ras mice to generate mice that express activated Ras and differ in their Gadd45a status. Using this mouse model, we show that the loss of Gadd45a accelerates Ras-driven mammary tumor formation, exhibiting increased growth rates and a more aggressive histologic phenotype. Moreover, it is shown that accelerated Ras-driven tumor formation in the absence of Gadd45a results in both a decrease in apoptosis, which is linked to a decrease in c-Jun NH(2)-terminal kinase (JNK) activation, and a decrease in Ras-induced senescence, which is correlated with a decrease in p38 kinase activation. Altogether, these results provide a novel model for the tumor-suppressive function of Gadd45a in the context of Ras-driven breast carcinogenesis, showing that Gadd45a elicits its function through activation of the stress-induced JNK and p38 kinases, which contribute to increase in apoptosis and Ras-induced senescence.
Tront
Jennifer S
JS
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
Hoffman
Barbara
B
Liebermann
Dan A
DA
D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D016922:Cellular Senescence; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D011905:Genes, ras; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000473:pathology* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D017931:DNA Primers; D009687:Nuclear Proteins; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins