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Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
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A mechanism misregulating p27 in tumors discovered in a functional genomic screen

Carrie M Garrett-Engele1, Michael A Tasch, Harry C Hwang

  • 1Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

Plos Genetics
|December 12, 2007
PubMed

Insights

The inhibitor of DNA binding 3 (Id3) gene represses the tumor suppressor p27(KIP1) during lymphomagenesis. This transcriptional repression is a novel mechanism causing decreased p27 protein levels in tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • The cyclin-dependent kinase inhibitor p27(KIP1) acts as a tumor suppressor, and its reduced levels indicate poor prognosis in human cancers.
  • Unlike other tumor suppressors, the p27 gene is seldom mutated, suggesting its downregulation results from misregulation rather than gene loss.

Purpose of the Study:

  • To identify genes regulating p27 expression during lymphomagenesis using a functional genomic screen.
  • To elucidate the mechanism behind decreased p27 protein levels in tumors.

Main Methods:

  • Functional genomic screen in p27(+/-) mice to identify regulatory genes.
  • Retroviral tagging strategy to pinpoint transcription factors involved in p27 gene regulation.
  • Validation of identified genes as transcriptional repressors or activators of p27.

Main Results:

  • Decreased p27 expression in tumors was attributed to altered p27 gene transcription.
  • The inhibitor of DNA binding 3 (Id3) was identified as a transcriptional repressor of p27.
  • p27 was confirmed as a downstream target of Id3 in src-family kinase Lck-driven thymic lymphomagenesis.
  • p27 plays a crucial role in Lck-dependent thymic maturation during normal T-cell development.

Conclusions:

  • Transcriptional repression of p27 by Id3 is a newly identified mechanism contributing to reduced p27 protein levels in tumors.
  • Understanding this Id3-p27 interaction provides insights into lymphomagenesis and T-cell development.

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