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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

Transforming growth factor beta-induced cell cycle arrest of human hematopoietic cells requires p57KIP2 up-regulation

Joseph M Scandura1, Piernicola Boccuni, Joan Massagué

  • 1Molecular Pharmacology and Chemistry Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 13, 2004
PubMed

Insights

Transforming growth factor beta (TGFbeta) halts hematopoietic cell growth by upregulating p57KIP2 (p57). This mechanism is crucial for cell cycle arrest and may explain p57 silencing in blood cancers.

Area of Science:

  • Hematology
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • Transforming growth factor beta (TGFbeta) negatively regulates hematopoiesis.
  • Mechanisms of TGFbeta-induced cell cycle arrest and stem cell quiescence in hematopoietic cells are not fully understood.
  • Cyclin-dependent kinase inhibitors p15INK4b and p21WAF1 mediate TGFbeta cytostasis in epithelial cells, but not hematopoietic cells.

Purpose of the Study:

  • To identify the specific cyclin-dependent kinase inhibitor induced by TGFbeta in human hematopoietic cells.
  • To elucidate the molecular pathway by which TGFbeta mediates cytostatic effects on hematopoietic cells.
  • To investigate the role of p57KIP2 in TGFbeta-induced cell cycle arrest and its potential link to hematologic malignancies.

Main Methods:

  • Primary human hematopoietic cells were used.
  • Microarray analysis identified differentially expressed genes.
  • Small interfering RNAs (siRNAs) were employed to assess gene function.
  • Promoter analysis investigated transcriptional regulation.

Main Results:

  • p57KIP2 (p57) was identified as the sole cyclin-dependent kinase inhibitor upregulated by TGFbeta in hematopoietic cells.
  • TGFbeta-induced p57 upregulation precedes G1 cell cycle arrest and is transcriptionally dependent.
  • siRNA-mediated knockdown of p57 blocked TGFbeta's cytostatic effects and increased basal proliferation.
  • p57 promoter hypermethylation is frequent in hematologic malignancies, suggesting a link to silenced expression.

Conclusions:

  • TGFbeta mediates cytostasis in human hematopoietic cells primarily through the induction of p57KIP2.
  • p57KIP2 is essential for TGFbeta-induced G1 cell cycle arrest in these cells.
  • The findings suggest a mechanism for TGFbeta's role in hematopoiesis and provide a potential explanation for p57 silencing in hematologic malignancies.

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