The MCT-1 Oncogene Product Impairs Cell Cycle Checkpoint Control and Transforms Human Mammary Epithelial Cells

Oncogene. 2005 Jul 21;24(31):4956-64. doi: 10.1038/sj.onc.1208680.

Abstract

Multiple copies in T-cell maligancy (MCT-1) is a putative oncogene initially identified in a human T-cell lymphoma. Forced expression of MCT-1 has recently been shown to induce cell transformation and proliferation, as well as to activate survival-related PI-3K/AKT pathways protecting cells from apoptosis. MCT-1 protein is stabilized in response to DNA damage. The impact of MCT-1 overexpression on DNA damage response remains unknown. Here, we show that MCT-1 deregulates cell cycle checkpoints. The phosphorylation of genomic stabilizers H2AX and NBS1 are enhanced in MCT-1-overexpressing cells. Forced expression of MCT-1 significantly increases the number of DNA damage-induced foci involving gamma-H2AX and 53BP1. In MCT-1-overexpressing cells, the proportion of S-phase cell population is preferentially increased after exposure to gamma-irradiation compared to controls. Knockdown of endogenous MCT-1 using an siRNA approach attenuates the H2AX phosphorylation and the G1/S checkpoint defect. Furthermore, MCT-1 is capable of transforming immortalized human mammary epithelial cells and promoting genomic instability. These data shed light on the role of MCT-1 in the cellular response to DNA damage and its involvement in malignant transformation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Base Sequence
  • Breast / cytology*
  • Breast Neoplasms
  • Cell Cycle / physiology*
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic*
  • DNA Damage
  • DNA Primers
  • Epithelial Cells / cytology*
  • Epithelial Cells / pathology
  • Female
  • Humans
  • Lymphoma, T-Cell / genetics
  • Oncogene Proteins / metabolism
  • Oncogene Proteins / physiology*
  • Oncogenes*
  • Plasmids
  • RNA Interference

Substances

  • Cell Cycle Proteins
  • DNA Primers
  • MCTS1 protein, human
  • Oncogene Proteins