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Cdc7-Dbf4 kinase overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation

Dorine Bonte1, Charlotta Lindvall, Hongyu Liu

  • 1Laboratories of Chromosome Replication, Van Andel Research Institute, Grand Rapids, MI 49503, USA.

Neoplasia (New York, N.Y.)
|August 21, 2008
PubMed

Insights

Increased Cdc7-Dbf4 protein levels, crucial for DNA replication initiation, were observed in many human tumors but not normal tissues. This suggests Cdc7-Dbf4 may be a common factor in human malignancies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Cdc7 is a serine/threonine kinase vital for initiating DNA replication.
  • Cdc7 functions with its regulatory subunit Dbf4, forming the Cdc7-Dbf4 complex.
  • The Cdc7-Dbf4 complex is regulated by the Ataxia telangectasia and RAD3-related (ATR) kinase, which responds to DNA damage.

Purpose of the Study:

  • To investigate the expression levels of Cdc7 and Dbf4 proteins in human tumor cell lines and primary tumors.
  • To determine the correlation between Cdc7-Dbf4 expression and p53 status in cancer.

Main Methods:

  • Western blot analysis to assess protein levels.
  • Gene copy number analysis for DBF4.
  • Analysis of clinical tumor samples and cancer cell lines.

Main Results:

  • Cdc7 protein was significantly elevated in approximately 50% of tested human tumor cell lines and in primary breast, colon, and lung tumors, compared to normal tissues.
  • Increased Dbf4 abundance often accompanied elevated Cdc7 levels, with some tumor cell lines showing amplified DBF4 gene copies.
  • A strong correlation was found between p53 loss and increased CDC7 and DBF4 expression in breast cancers and cell lines.

Conclusions:

  • Elevated Cdc7-Dbf4 protein levels are a frequent finding in human malignancies.
  • The p53 tumor suppressor pathway appears to influence Cdc7-Dbf4 expression.
  • The Cdc7-Dbf4 complex represents a potential target in cancer therapy.

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