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Hcdc4 gene mutations in endometrial cancer

Academic Article
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Overview

authors

  • Spruck, C. H.
  • Strohmaier, H.
  • Sangfelt, O.
  • Muller, H. M.
  • Hubalek, M.
  • Muller-Holzner, E.
  • Marth, C.
  • Widschwendter, M.
  • Reed, Steven

publication date

  • August 2002

journal

  • Cancer Research  Journal

abstract

  • Cyclin-dependent kinase 2 activated by cyclin E is involved in the initiation of DNA replication and other S phase functions. Consistent with this role, cyclin E protein accumulates at the G1-S phase transition and declines during early S phase. This profile of expression is the result of periodic transcription and ubiquitin-mediated proteolysis directed by SCF(hCdc4). However, in many types of human tumors cyclin E protein is elevated and deregulated relative to the cell cycle by an unknown mechanism. Here, we show that the F-box protein hCdc4 that targets cyclin E to the SCF (Skp1-Cull-F-box) protein ubiquitin ligase is mutated in at least 16% of human endometrial tumors. Mutations were found either in the substrate-binding domain of the protein or at the amino terminus, suggesting a critical role for the region of hCdc4 upstream of the F-box. hCDC4 gene mutations were accompanied by loss of heterozygosity and correlated with aggressive disease. The hCDC4 gene is localized to chromosome region 4q32, which is deleted in over 30% of human tumors. Our results show that the hCDC4 gene is mutated in primary human tumors and suggest that it may function as a tumor suppressor in the genesis of many human cancers.

subject areas

  • Adenocarcinoma
  • Blotting, Northern
  • Cell Cycle Proteins
  • Cyclin E
  • Endometrial Neoplasms
  • F-Box Proteins
  • Female
  • HeLa Cells
  • Humans
  • Mutation
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitin-Protein Ligases
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Identity

International Standard Serial Number (ISSN)

  • 0008-5472

PubMed ID

  • 12183400
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Additional Document Info

start page

  • 4535

end page

  • 4539

volume

  • 62

issue

  • 16

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