Differential Contribution of Puma and Noxa in Dual Regulation of p53-mediated Apoptotic Pathways

EMBO J. 2006 Oct 18;25(20):4952-62. doi: 10.1038/sj.emboj.7601359. Epub 2006 Oct 5.

Abstract

The activation of tumor suppressor p53 induces apoptosis or cell cycle arrest depending on the state and type of cell, but it is not fully understood how these different responses are regulated. Here, we show that Puma and Noxa, the well-known p53-inducible proapoptotic members of the Bcl-2 family, differentially participate in dual pathways of the induction of apoptosis. In normal cells, Puma but not Noxa induces mitochondrial outer membrane permeabilization (MOMP), and this function is mediated in part by a pathway that involves calcium release from the endoplasmic reticulum (ER) and the subsequent caspase activation. However, upon E1A oncoprotein expression, cells also become susceptible to MOMP induction by Noxa, owing to their sensitization to the ER-independent pathway. These findings offer a new insight into differential cellular responses induced by p53, and may have therapeutic implications in cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenovirus E1A Proteins / genetics
  • Adenovirus E1A Proteins / metabolism
  • Animals
  • Apoptosis Regulatory Proteins
  • Apoptosis* / genetics
  • Calcium / metabolism
  • Calcium Signaling* / genetics
  • Caspases / genetics
  • Caspases / metabolism
  • Cell Membrane Permeability / genetics
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism
  • Enzyme Activation / genetics
  • Gene Expression
  • Mice
  • Mitochondrial Membranes / metabolism
  • NIH 3T3 Cells
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Adenovirus E1A Proteins
  • Apoptosis Regulatory Proteins
  • PUMA protein, mouse
  • Pmaip1 protein, mouse
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Caspases
  • Calcium