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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

Inhibition of p53-induced apoptosis without affecting expression of p53-regulated genes

Joseph Lotem1, Hilah Gal, Rachel Kama

  • 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.

Proceedings of the National Academy of Sciences of the United States of America
|May 14, 2003
PubMed

Insights

Interleukin 6 (IL-6) and thapsigargin (TG) inhibit p53-induced apoptosis without broadly affecting p53 gene regulation. These compounds promote tumor development and resistance to cancer therapies.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • Wild-type p53 is a tumor suppressor protein that induces apoptosis (programmed cell death).
  • Interleukin 6 (IL-6) and thapsigargin (TG) are known to inhibit p53-mediated apoptosis.
  • The precise mechanism by which IL-6 and TG inhibit p53-induced apoptosis remains unclear.

Purpose of the Study:

  • To elucidate the mechanism by which IL-6 and TG inhibit wild-type p53-induced apoptosis.
  • To determine if IL-6 and TG broadly affect p53's transcriptional regulatory functions.
  • To identify alternative gene expression pathways activated by IL-6 and TG.

Main Methods:

  • DNA microarray analysis was employed to examine gene expression profiles.
  • Clustering analysis was performed on 1,786 genes showing altered expression after p53 activation.
  • Gene expression was analyzed in the presence and absence of IL-6 or TG.

Main Results:

  • IL-6 and TG did not broadly inhibit the ability of wild-type p53 to up-regulate or down-regulate gene expression.
  • The expression of known p53 target genes involved in apoptosis was unaffected by IL-6 and TG.
  • IL-6 and TG activated distinct p53-independent gene expression pathways, including antiapoptotic and differentiation-associated genes.

Conclusions:

  • IL-6 and TG inhibit p53-mediated apoptosis by bypassing p53's transcriptional control.
  • These compounds activate alternative signaling pathways that promote cell survival and differentiation.
  • The ability of IL-6 and TG to inhibit apoptosis without affecting p53 gene regulation may contribute to tumor development and resistance to therapy.

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