Human Bcl-2 activates ERK signaling pathway to regulate activating protein-1, lens epithelium-derived growth factor and downstream genes.
The proto-oncogene, bcl-2, has various functions besides its role in protecting cells from apoptosis. One of the functions is to regulate expression of other genes. Previous studies have demonstrated that Bcl-2 regulates activities of several important transcription factors including NF-kappaB and p53, and also their downstream genes. In our recent studies, we reported that Bcl-2 substantially downregulates expression of the endogenous alphaB-crystallin gene through modulating the transcriptional activity of lens epithelium-derived growth factor (LEDGF). In the present communication, we report that human Bcl-2 can positively regulate expression of the proto-oncogenes c-jun and c-fos. Moreover, it enhances the DNA binding activity and transactivity of the activating protein-1 (AP-1). Furthermore, we present evidence to show that Bcl-2 can also activate both ERK1 and ERK2 MAP kinases. Inhibition of the activities of these kinases or the upstream activating kinases by pharmacological inhibitors or dominant-negative mutants abolishes the Bcl-2-mediated regulation of AP-1, LEDGF and their downstream genes. Together, our results demonstrate that through activation of the ERK kinase signaling pathway, Bcl-2 regulates the transcriptional activities of multiple transcription factors, and hence modulates the expression of their downstream genes. Thus, our results provide a mechanism to explain how Bcl-2 may regulate expression of other genes.
College of Life Sciences, Hunan Normal University, Changsha, PR China.
Hao
H
Feng
Hua
H
Xiang
Ying-Wei
YW
Mao
Juan
J
Wang
Jin-Ping
JP
Liu
Xiao-Qin
XQ
Huang
Yan
Y
Liu
Shao-Jun
SJ
Liu
Chen
C
Luo
Xuan-Jie
XJ
Zhang
Yun
Y
Liu
David Wan-Cheng
DW
Li
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D015342:DNA Probes; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D005822:Genetic Vectors; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D007908:Lens, Crystalline / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014162:Transfection
D015342:DNA Probes; D036341:Intercellular Signaling Peptides and Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; C119380:lens epithelium-derived growth factor; D020928:Mitogen-Activated Protein Kinases