c-Fos is a mediator of the c-myc-induced apoptotic signaling in serum-deprived hepatoma cells via the p38 mitogen-activated protein kinase pathway.
The proto-oncogene c-myc encodes a transcription factor that plays a pivotal role in cell proliferation, differentiation, and apoptosis. The signaling mechanism of c-Myc-induced apoptosis was investigated on the human hepatoma Huh7 cells under growth factor-deprived conditions. The apoptotic process did not involve p53. Rather it was dependent on the expression of c-Fos. Activation of caspases 3 and 9 and down-regulation of Bcl2 were observed in the apoptotic process, indicating it to be a mitochondria-dependent event. An increase in the p38 mitogen-activated protein kinase that was mediated by a Rac1-dependent and cdc42-independent pathway eventually leading to up-regulation of c-Fos activity was also observed. Deletion analysis of the promoter region of the c-fos gene indicated that the ATF2-responsive element conferred the Myc-induced expression of c-Fos. Co-expression of the dominant-negative mutants of c-Fos, p38, and Rac1 blocked the Myc-mediated apoptosis. SB20358, a chemical inhibitor of p38 pathway, also specifically blocked the apoptotic signaling by c-Myc. Furthermore, co-expression of the hepatitis B virus X protein (HBx) along with Myc abrogated the apoptotic signals. The HBx expression was associated with an increase in the levels of phosphorylated AKT and down-regulation of c-Fos by Myc. Thus, c-Fos seems be a new mediator of c-Myc-induced apoptosis.
Kalra
Neetu
N
Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India.
Kumar
Vijay
V
D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000502:physiology; D054334:Viral Regulatory and Accessory Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins / Q000502:physiology
D016895:Culture Media, Serum-Free; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020741:rho GTP-Binding Proteins