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The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3beta and cAMP-responsive

M D'Amico1, J Hulit, D F Amanatullah

  • 1Albert Einstein Cancer Center, Departments of Developmental and Molecular Biology Medicine and Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

The Journal of Biological Chemistry
|August 1, 2000
PubMed

Insights

Integrin-linked kinase (ILK) directly induces the cyclin D1 gene in mammary cells, involving the CREB signaling pathway. This discovery sheds light on cyclin D1 regulation in breast cancer.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Cyclin D1 is a key regulator of cell cycle progression, often overexpressed in breast tumors.
  • Integrin-linked kinase (ILK) is implicated in promoting anchorage-independent growth and cancer progression.

Purpose of the Study:

  • To investigate the role of ILK in regulating cyclin D1 gene expression in mammary epithelial cells.
  • To elucidate the signaling pathways involved in ILK-mediated cyclin D1 induction.

Main Methods:

  • Overexpression of ILK in mammary epithelial cells.
  • Analysis of cyclin D1 promoter activity using reporter assays.
  • Site-directed mutagenesis of the CREB/ATF-2 binding site.
  • Inhibition of various signaling pathways (PI 3-kinase, AKT, p38, ERK, JNK).
  • Western blot analysis and chromatin immunoprecipitation assays.
  • Wnt-1 overexpression studies in cell culture and transgenic mice.

Main Results:

  • ILK overexpression elevates cyclin D1 protein and directly induces cyclin D1 gene expression.
  • ILK-induced cyclin D1 promoter activity depends on a CREB/ATF-2 binding site.
  • Inhibition of PI 3-kinase/AKT pathway, but not p38/ERK/JNK, reduced ILK-induced cyclin D1.
  • ILK activates CREB and promotes its binding to the cyclin D1 promoter.
  • Wnt-1 overexpression increases ILK activity and cyclin D1 levels.

Conclusions:

  • The cyclin D1 gene is regulated by Wnt-1 and ILK signaling pathways.
  • ILK induces cyclin D1 expression in mammary epithelial cells via the CREB signaling pathway.

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