Abstract
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.
Highlights
Cancer pathogenesis is involved in multiple pathways, including inactivation of tumor suppressors, activation of oncogenes, loss of cell differentiation, augmentation of proliferative activity, alteration of hormone receptor status, and increase of metastatic potential [1]
P53 and p21 protein levels are decreased by MCT-1–overexpressing cells (MCT-1) overexpression in response to bleomycin (BLM) and etoposide (ETO) genotoxicity, and their reductions are attenuated by the inhibition of MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) signaling
We speculate that the oncogenic chromosome aberrations and tumorigenicity will enormously amplify while putting MCT-1 oncogenic stress in already p53-null or p53-deficient cells, which cannot
Summary
Cancer pathogenesis is involved in multiple pathways, including inactivation of tumor suppressors, activation of oncogenes, loss of cell differentiation, augmentation of proliferative activity, alteration of hormone receptor status, and increase of metastatic potential [1]. The fine balance between the proto-oncogene function and tumor suppressor activity plays a critical role in regulation of cell growth, cell cycle, and genome stabilization. Mitotic checkpoint controls the integrity of chromosome structure [2,3,4,5]. This checkpoint monitors chromosome alignment during metaphase and prevents premature progression through mitosis. It can stop mitotic cells from entering anaphase and prohibit chromosomes from moving toward the spindle poles. Cells that have been encountered with mitotic catastrophes can end up either entering apoptosis or exiting from mitosis with multinucleation or chromosome aberrations. The consequential chromosome instability comprises gains or losses of whole chromosome(s) (aneuploidy), translocations, amplifications/deletions, or breaks [9,10,11]
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