Human Bcl-2 activates ERK signaling pathway to regulate activating protein-1, lens epithelium-derived growth factor and downstream genes

Oncogene. 2004 Sep 23;23(44):7310-21. doi: 10.1038/sj.onc.1208041.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • DNA Probes
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • Gene Expression Regulation / physiology*
  • Genes, fos / genetics
  • Genes, jun / genetics
  • Genetic Vectors
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Lens, Crystalline / cytology
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinases / metabolism*
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Rabbits
  • Rats
  • Recombinant Proteins / metabolism
  • Transcription Factor AP-1 / genetics*
  • Transfection

Substances

  • DNA Probes
  • Intercellular Signaling Peptides and Proteins
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • Transcription Factor AP-1
  • lens epithelium-derived growth factor
  • Mitogen-Activated Protein Kinases