The MCT-1 oncogene product impairs cell cycle checkpoint control and transforms human mammary epithelial cells.
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.
Hsu
Hsin-Ling
HL
Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine and the Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA.
Shi
Bo
B
Gartenhaus
Ronald B
RB
D001483:Base Sequence; D001940:Breast / Q000166:cytology*; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D017931:DNA Primers; D004847:Epithelial Cells / Q000166:cytology* / Q000473:pathology; D005260:Female; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics; D015513:Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D009857:Oncogenes; D010957:Plasmids; D034622:RNA Interference
D018797:Cell Cycle Proteins; D017931:DNA Primers; C115081:MCTS1 protein, human; D015513:Oncogene Proteins