PUMA and BIM are required for oncogene inactivation-induced apoptosis Journal Article


Authors: Bean, G. R.; Ganesan, Y. T.; Dong, Y.; Takeda, S.; Liu, H.; Chan, P. M.; Huang, Y.; Chodosh, L. A.; Zambetti, G. P.; Hsieh, J. J. D.; Cheng, E. H. Y.
Article Title: PUMA and BIM are required for oncogene inactivation-induced apoptosis
Abstract: The clinical efficacy of tyrosine kinase inhibitors supports the dependence of distinct subsets of cancers on specific driver mutations for survival, a phenomenon called "oncogene addiction." We demonstrate that PUMA and BIM are the key apoptotic effectors of tyrosine kinase inhibitors in breast cancers with amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) and lung cancers with epidermal growth factor receptor (EGFR) mutants. The BH3 domain containing proteins BIM and PUMA can directly activate the proapoptotic proteins BAX and BAK to permeabilize mitochondria, leading to caspase activation and apoptosis. We delineated the signal transduction pathways leading to the induction of BIM and PUMA by tyrosine kinase inhibitors. Inhibition of the mitogen-activated or extracellular signal-regulated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway caused increased abundance of BIM, whereas antagonizing the phosphoinositide 3-kinase (PI3K)-AKT pathway triggered nuclear translocation of the FOXO transcription factors, which directly activated the PUMA promoter. In a mouse breast tumor model, the abundance of PUMA and BIM was increased after inactivation of HER2. Moreover, deficiency of Bim or Puma impaired caspase activation and reduced tumor regression caused by inactivation of HER2. Similarly, deficiency of Puma impeded the regression of EGFRL858R-driven mouse lung tumors upon inactivation of the EGFR-activating mutant. Overall, our study identified PUMA and BIM as the sentinels that interconnect kinase signaling networks and the mitochondrion-dependent apoptotic program, which offers therapeutic insights for designing novel cell death mechanism-based anticancer strategies. Copyright 2008 by the American Association for the Advancement of Science.
Journal Title: Science Signaling
Volume: 6
Issue: 268
ISSN: 1945-0877
Publisher: American Association for the Advancement of Science  
Date Published: 2013-03-26
Start Page: ra20
Language: English
PROVIDER: scopus
PUBMED: 23532334
DOI: 10.1126/scisignal.2003483
PMCID: PMC3753585
DOI/URL:
Notes: --- - Cited By (since 1996):2 - "Export Date: 1 May 2013" - ":doi 10.1126/scisignal.2003483" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Yiyu Dong
    17 Dong
  2. Yafen Huang
    2 Huang
  3. Shugaku Takeda
    16 Takeda
  4. James J Hsieh
    114 Hsieh
  5. Han Liu
    12 Liu
  6. Emily H Cheng
    56 Cheng
  7. Gregory Bean
    1 Bean
  8. Po M Chan
    2 Chan