Immediate early up-regulation of bax expression by p53 but not TGFβ1: A paradigm for distinct apoptotic pathways

Muthu Selvakumaran, Hsueh Kung Lin, Toshiyuki Miyashita, Hong Gang Wang, Stanislow Krajewski, John C. Reed, Barbara Hoffman, Dan Liebermann

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Abstract

Recently, both Bcl-2, which promotes cell survival, and Bax, which promotes cell death, have been implicated as major players in the control of apoptotic pathways, and it has been suggested that the ratio of Bcl-2 and Bax protein controls the relative susceptibility of cells to death stimuli. We have used M1 myeloid leukemia cells and genetically engineered M1 variants as a model system to study apoptosis induced by two distinct apoptotic stimuli. This includes apoptosis induced by activation of wild type p53 function of a temperature sensitive p53 transgene expressed in M1 cells, which do not express endogenous p53, and apoptosis induced by TGFβ1. It is shown that the kinetics of apoptosis induced by p53 is more rapid than apoptosis induced by TGFβ1. It is also shown that ectopic expression of Bcl-2, at levels which blocked TGFβ1-induced apoptosis of M1 cells, delayed, but did not block, p53-induced apoptosis. Both p53 and TGFβ1 down-regulated endogenous Bcl-2 expression, but only p53 up-regulated Bax expression, where bax has been identified as a p53 immediate early response gene. Thus, the p53-mediated up-regulation of Bax may provide at least a partial explanation for the more rapid rate of apoptosis induced by p53 compared to by TGFβ1, as well as for the ineffectiveness of ectopoic Bcl-2 to abrogate p53-mediated apoptosis. These findings provide first insights to the molecular mechanisms which mediate p53-induced apoptosis, identifying bax and bcl-2 as p53 regulated genes, and serve as a paradigm of how the intracellular balance of Bcl-2 to Bax is differentially altered by distinct death stimuli.

Original languageEnglish (US)
Pages (from-to)1791-1798
Number of pages8
JournalOncogene
Volume9
Issue number6
StatePublished - Jun 1 1994

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Selvakumaran, M., Lin, H. K., Miyashita, T., Wang, H. G., Krajewski, S., Reed, J. C., Hoffman, B., & Liebermann, D. (1994). Immediate early up-regulation of bax expression by p53 but not TGFβ1: A paradigm for distinct apoptotic pathways. Oncogene, 9(6), 1791-1798.