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Differential effects of transforming growth factor on cell cycle regulatory molecules in human myeloid leukemia cells

X Hu1, X Zhang, Q Zhong

  • 1Interdisciplinary Oncology Program, University of South Florida, and H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA. hu@moffitt.usf.esu

Oncogene
|November 1, 2001
PubMed

Insights

Transforming Growth Factor beta (TGF beta) inhibits human myeloid leukemia cell growth by downregulating key cell cycle proteins. It also affects p27(kip1) activity, impacting cell cycle regulation through multiple pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • Transforming Growth Factor beta (TGF beta) is known to regulate cell growth and differentiation.
  • Its role in inhibiting human myeloid leukemia cell lines requires further mechanistic elucidation.

Purpose of the Study:

  • To investigate the molecular mechanisms by which TGF beta 1 inhibits the growth of human myeloid leukemia cell lines.
  • To determine the role of cell cycle regulatory proteins, including cyclins and cyclin-dependent kinases (CDKs), and p27(kip1) in TGF beta 1-mediated growth inhibition.

Main Methods:

  • Cell cycle analysis (G1 arrest).
  • Western blotting to assess protein expression levels (cyclin D2, D3, A, E, cdk2, cdk4, p27(kip1)).
  • Kinase activity assays.
  • Immunodepletion and antisense cDNA experiments to evaluate protein function.

Main Results:

  • TGF beta 1 induced G1 arrest and significantly downregulated cyclins D2, D3, A, cdk4, and cdk2 expression, decreasing their kinase activities.
  • TGF beta 1 upregulated p27(kip1) accumulation, but its association with cell cycle inhibitors was reduced, suggesting it's not the primary cause of kinase downregulation.
  • TGF beta 1 upregulated cyclin E-associated p27(kip1) without affecting cyclin E expression; p27(kip1) immunodepletion rescued cyclin E kinase activity in treated cells.
  • p27(kip1) immunodepletion from cdk2 immunoprecipitates reduced cdk2 kinase activity in both proliferating and TGF beta 1-treated cells.
  • TGF beta 1 and p27(kip1) antisense cDNA showed synergistic/additive inhibition on cdk2 but not cyclin E kinase activity.

Conclusions:

  • TGF beta 1-mediated growth inhibition in human myeloid leukemia cells involves multiple pathways.
  • p27(kip1) exhibits opposing effects on cdk2 and cyclin E kinase activity in response to TGF beta 1, highlighting its complex role in cell cycle regulation.

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