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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53

Chun-Qi Li1, Ana I Robles, Christin L Hanigan

  • 1Biological Engineering Division and Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, USA.

Cancer Research
|May 6, 2004
PubMed

Insights

Nitric oxide (NO) induces apoptosis in human cells through p53-dependent pathways, activating mitochondrial and Fas receptor signaling. Loss of p53 function prevents this NO-induced cell death, highlighting p53

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • The tumor suppressor protein p53 plays a critical role in regulating apoptosis, a process crucial for eliminating damaged cells.
  • Inactivating mutations in p53 are common in human cancers and often lead to resistance to apoptosis.
  • Nitric oxide (NO) is a signaling molecule involved in various physiological processes, including the induction of apoptosis.

Purpose of the Study:

  • To investigate the molecular mechanisms by which nitric oxide (NO) induces apoptosis in human lymphoblastoid cells.
  • To characterize the role of p53 in mediating NO-induced apoptosis.
  • To elucidate the specific apoptotic signaling pathways activated by NO in a p53-dependent manner.

Main Methods:

  • Utilized cDNA microarray expression analysis to assess global gene expression changes.
  • Employed immunoblotting to examine protein level alterations.
  • Compared p53-wild-type (TK6) and p53-mutant (WTK1) human lymphoblastoid cell lines.

Main Results:

  • NO exposure induced a p53-mediated transcriptional response in wild-type cells, upregulating key apoptosis-related genes like Fas/CD95, PUMA, and NOXA.
  • NO modulated both mitochondrial and death receptor-mediated apoptotic pathways, including down-regulation of inhibitor of apoptosis proteins and increased Fas/CD95 levels.
  • Activation of caspases and cleavage of PARP were observed exclusively in p53-wild-type cells, indicating p53-dependent apoptosis induction.
  • Smac release from mitochondria occurred in both cell types, but apoptosis-inducing factor and endonuclease G release were specific to p53-wild-type cells.

Conclusions:

  • NO exposure triggers a complex, p53-dependent apoptotic response involving both mitochondrial and Fas receptor pathways.
  • The loss of p53 function abrogates NO-induced apoptosis, underscoring the critical role of p53 in this process.
  • These findings provide insights into how p53 mutations contribute to cancer cell survival under NO-inducing conditions.

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