Selective induction of p53 and chemosensitivity in RB-deficient cells by E1A mutants unable to bind the RB-related

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Analysis of Cell Cycle Position in Mammalian Cells
12:19

Analysis of Cell Cycle Position in Mammalian Cells

Published on: January 21, 2012

A V Samuelson1, S W Lowe

  • 1Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 29, 1997
PubMed

Insights

Adenovirus E1A oncoprotein enhances cancer drug sensitivity by inducing apoptosis. This effect is linked to p53 accumulation and requires the retinoblastoma protein (RB) pathway inactivation.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cellular Biology

Background:

  • Adenovirus E1A oncoprotein sensitizes cells to apoptosis and anticancer agents.
  • E1A expression leads to p53 protein accumulation, potentiating drug-induced apoptosis.

Purpose of the Study:

  • To investigate the mechanisms by which E1A promotes chemosensitivity.
  • To identify specific E1A functions and protein interactions critical for inducing apoptosis and sensitizing cells to chemotherapy.

Main Methods:

  • Utilized recombinant retroviruses to introduce E1A mutants into primary human and mouse fibroblasts.
  • Analyzed E1A's role in genetically normal cells, independent of adenovirus infection.
  • Assessed apoptosis and chemosensitivity in cells with various E1A mutations and in mice deficient in RB family proteins.

Main Results:

  • Mutations disrupting apoptosis and chemosensitivity correlated with E1A's interaction with p300/CBP or retinoblastoma protein (RB) families.
  • E1A mutants unable to bind RB, p107, and p130 conferred chemosensitivity to RB-deficient mouse fibroblasts, but not to p107 or p130 deficient cells.
  • Inactivation of RB, but not p107 or p130, is essential for E1A-induced chemosensitivity.
  • E1A functions promoting drug-induced apoptosis also induce p53 accumulation.

Conclusions:

  • p53 accumulation and chemosensitivity are directly linked to E1A's oncogenic activity.
  • E1A-induced apoptosis and chemosensitivity are mediated through RB pathway inactivation.
  • Identified a potential strategy for selectively inducing apoptosis in RB-deficient tumor cells using E1A-related mechanisms.

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