Overexpression of the pituitary tumor transforming gene induces p53-dependent senescence through activating DNA damage response pathway in normal human fibroblasts.
Pituitary tumor transforming gene (PTTG1, securin) is involved in cell-cycle control through inhibition of sister-chromatid separation. Elevated levels of PTTG1 were found to be associated with many different tumor types that might be involved in late stage tumor progression. However, the role of PTTG1 in early stage of tumorigenesis is unclear. Here we utilized the adenovirus expression system to deliver PTTG1 into normal human fibroblasts to evaluate the role of PTTG1 in tumorigenesis. Expressing PTTG1 in normal human fibroblasts inhibited cell proliferation. Several senescence-associated (SA) phenotypes including increased SA-beta-galactosidase activities, decreased bromodeoxyuridine incorporation, and increased SA-heterochromatin foci formation were also observed in PTTG1-expressing cells, indicating that PTTG1 overexpression induced a senescent phenotype in normal cells. Significantly, the PTTG1-induced senescence is p53-dependent and telomerase-independent, which is distinctively different from that of replicative senescence. The mechanism of PTTG1-induced senescence was also analyzed. Consistent with its role in regulating sister-chromatid separation, overexpression of PTTG1 inhibited the activation of separase. Consequently, the numbers of cells with abnormal nuclei morphologies and chromosome separations were increased, which resulted in activation of the DNA damage response. Thus, we concluded that PTTG1 overexpression in normal human fibroblasts caused chromosome instability, which subsequently induced p53-dependent senescence through activation of DNA-damage response pathway.
Hsu
Yi-Hsin
YH
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan.
Liao
Li-Jen
LJ
Yu
Chuan-Hang
CH
Chiang
Chun-Pin
CP
Jhan
Jing-Ru
JR
Chang
Lien-Cheng
LC
Chen
Yann-Jang
YJ
Lou
Pei-Jen
PJ
Lin
Jing-Jer
JJ
D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D043171:Chromosomal Instability / Q000235:genetics; D004249:DNA Damage; D010450:Endopeptidases / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D064249:Securin; D064247:Separase; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; D064249:Securin; D016159:Tumor Suppressor Protein p53; C578002:pituitary tumor-transforming protein 1, human; D010450:Endopeptidases; C577987:ESPL1 protein, human; D064247:Separase
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