A tumor suppressor function for caspase-2

Lien Ha Ho, Robyn Taylor, Loretta Dorstyn, Dimitrios Cakouros, Philippe Bouillet, Sharad Kumar

Research output: Contribution to journalArticlepeer-review

124 Citations (Scopus)

Abstract

Apoptosis is mediated by the caspase family of proteases that act as effectors of cell death by cleaving many cellular substrates. Caspase-2 is one of the most evolutionarily conserved caspases, yet its physiological function has remained enigmatic because caspase-2-deficient mice develop normally and are viable. We report here that the caspase-2-/- mouse embryonic fibroblasts (MEFs) show increased proliferation. When transformed with E1A and Ras oncogenes, caspase-2-/- MEFs grew significantly faster than caspase-2+/+ MEFs and formed more aggressive and accelerated tumors in nude mice. To assess whether the loss of caspase-2 predisposes animals to tumor development, we used the mouse Eμ-Myc lymphoma model. Our findings suggest that loss of even a single allele of caspase-2 resulted in accelerated tumorigenesis, and this was further enhanced in caspase-2-/- mice. The caspase-2-/- cells showed resistance to apoptosis induced by chemotherapeutic drugs and DNA damage. Furthermore, caspase-2-/- MEFs had a defective apoptotic response to cell-cycle checkpoint regulation and showed abnormal cycling following γ-irradiation. These data show that loss of caspase-2 results in an increased ability of cells to acquire a transformed phenotype and become malignant, indicating that caspase-2 is a tumor suppressor protein.

Original languageEnglish
Pages (from-to)5336-5341
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number13
DOIs
Publication statusPublished or Issued - 31 Mar 2009

Keywords

  • Cell cycle
  • Cell survival
  • DNA damage
  • Proliferation
  • Tumorigenesis

ASJC Scopus subject areas

  • General

Cite this