Loss of p53 and MCT-1 overexpression synergistically promote chromosome instability and tumorigenicity.
MCT-1 oncoprotein accelerates p53 degradation by means of the ubiquitin-dependent proteolysis. Our present data show that induction of MCT-1 increases chromosomal translocations and deregulated G(2)-M checkpoint in response to chemotherapeutic genotoxin. Remarkably, increases in chromosome copy number, multinucleation, and cytokinesis failure are also promoted while MCT-1 is induced in p53-deficient cells. In such a circumstance, the Ras-mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-mitogen-activated protein kinase signaling activity and the expression of metastatic molecules are amplified. Given a p53-silencing background, MCT-1 malignantly transforms normal breast epithelial cells that are satisfactory for stimulating cell migration/adhesion and tumorigenesis. Detailed analyses of MCT-1 oncogenicity in H1299 p53-null lung cancer cells have shown that ectopically expressed MCT-1 advances xenograft tumorigenicity and angiogenesis, which cannot be completely suppressed by induction of p53. MCT-1 counteracts mutually with p53 at transcriptional levels. Clinical validations confirm that MCT-1 mRNA levels are differentially enriched in comparison between human lung cancer and nontumorigenic tissues. The levels of p53 mRNA are comparatively reduced in a subset of cancer specimens, which highly present MCT-1 mRNA. Our results indicate that synergistic promotions of chromosomal imbalances and oncogenic potency as a result of MCT-1 expression and p53 loss play important roles in tumor development.
National Health Research Institutes, Taiwan, Republic of China.
Ravi
R
Kasiappan
Hung-Ju
HJ
Shih
Kang-Lin
KL
Chu
Wei-Ti
WT
Chen
Hui-Ping
HP
Liu
Shiu-Feng
SF
Huang
Chik On
CO
Choy
Chung-Li
CL
Shu
Richard
R
Din
Jan-Show
JS
Chu
Hsin-Ling
HL
Hsu
D000782:Aneuploidy; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D043171:Chromosomal Instability; D020732:Cytogenetic Analysis; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D009153:Mutagens / Q000494:pharmacology; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; C115081:MCTS1 protein, human; D009153:Mutagens; D015513:Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; D019908:Proto-Oncogene Proteins c-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)