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Tumor suppressor TAp73 gene specifically responds to deregulated E2F activity in human normal fibroblasts

Eiko Ozono1, Hideyuki Komori, Ritsuko Iwanaga

  • 1Department of Molecular Virology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.

Genes to Cells : Devoted to Molecular & Cellular Mechanisms
|June 19, 2012
PubMed

Insights

Deregulated E2F activity, not normal growth signals, activates the tumor suppressor TAp73 gene. This occurs through specific E2F-responsive elements in the TAp73 promoter, highlighting a key tumor suppression pathway.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Cycle Regulation

Background:

  • Tumor suppression relies on distinguishing oncogenic from normal growth signals.
  • The transcription factor E2F, regulated by pRB, controls cell proliferation and tumor suppression.
  • The precise regulation of E2F targets, particularly growth-suppressive genes, remains incompletely understood.

Purpose of the Study:

  • To investigate the differential response of the TAp73 gene to physiological versus deregulated E2F activity.
  • To identify specific regulatory elements mediating TAp73 activation by aberrant E2F.
  • To elucidate the role of deregulated E2F in activating TAp73 within the context of RB1 deficiency.

Main Methods:

  • Analysis of TAp73 promoter activity in human normal fibroblasts under varying E2F activation conditions.
  • Identification and characterization of E2F-responsive elements (ERE73s) within the TAp73 promoter.
  • Assessment of ERE73s and TAp73 gene activation in RB1-deficient cancer cell lines with and without pRB re-introduction.

Main Results:

  • The tumor suppressor TAp73 gene specifically responds to deregulated E2F activity, not physiological E2F activation.
  • Novel E2F-responsive elements (ERE73s) were identified in the TAp73 promoter, capable of sensing deregulated E2F.
  • RB1-deficient cancer cells exhibited deregulated E2F activity, leading to ERE73s and TAp73 activation, which was reversed by pRB re-introduction.

Conclusions:

  • Deregulated E2F activity is a critical factor in activating the TAp73 gene.
  • The TAp73 gene and its promoter elements (ERE73s) function as sensors of aberrant E2F signaling.
  • These findings highlight the significance of deregulated E2F in activating TAp73, a crucial component of intrinsic tumor suppressor pathways.

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