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Noxa induces apoptosis in oncogene-expressing cells through catch-and-release mechanism operating between Puma and

Wataru Nakajima1, Nobuyuki Tanaka

  • 1Department of Molecular Oncology, Institute of Gerontology, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki 211-8533, Japan.

Biochemical and Biophysical Research Communications
|September 28, 2011
PubMed

Insights

Tumor suppressor p53 triggers apoptosis via Noxa and Puma. Oncogene E1A induces Puma, which Mcl-1 sequesters, priming cells for apoptosis. DNA damage then triggers Noxa, releasing Puma and activating cell death.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The tumor suppressor p53 is crucial for eliminating cells expressing oncogenes, primarily through inducing apoptosis.
  • Noxa and Puma are proapoptotic proteins that, when transcriptionally induced by p53, synergistically promote apoptosis.
  • Understanding the precise mechanisms of p53-mediated apoptosis is vital for cancer surveillance and therapy.

Purpose of the Study:

  • To investigate how the adenovirus oncogene E1A influences p53-dependent apoptosis.
  • To elucidate the roles of Noxa and Puma in E1A-induced apoptosis and their interactions with antiapoptotic proteins.
  • To understand the sequential activation of apoptotic pathways in response to oncogene expression and DNA damage.

Main Methods:

  • Adenovirus E1A expression in mouse embryonic fibroblasts (MEFs).
  • Analysis of p53-dependent gene expression (Puma, Noxa) using quantitative methods.
  • Co-immunoprecipitation to study protein-protein interactions (Puma-Mcl-1).
  • Western blotting to assess protein levels (Mcl-1, Bcl-X(L), Bax, Bak).
  • Mcl-1 knockdown experiments to evaluate its role in apoptosis.

Main Results:

  • E1A induced p53-dependent Puma expression, but not Noxa.
  • Induced Puma associated with Mcl-1, leading to Mcl-1 accumulation on mitochondria and reduced Bcl-X(L) levels.
  • Adriamycin treatment induced Noxa in E1A-expressing cells.
  • Mcl-1 knockdown induced apoptosis in E1A-expressing MEFs.
  • Noxa displaced Puma from Mcl-1, causing Mcl-1 degradation and activating Bax and Bak for apoptosis.

Conclusions:

  • Apoptosis in oncogene-expressing cells is regulated by the differential and sequential induction of Noxa and Puma.
  • Oncogene-induced Puma accumulation sensitizes cells to apoptosis by Mcl-1 sequestration.
  • Subsequent DNA damage triggers Noxa, which releases Puma from Mcl-1, initiating apoptosis via mitochondrial pathways.

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