Abstract
AbstractAberrant centrosome numbers are detected in virtually all cancersincreasing the risk for cell division errors and chromosomal instability. Deregulation of the centrosome duplication cycle is considered as the major contributing factor for abnormal amplification of centrosomes. p21Waf1 and p27Kip1, general CDK inhibitors by inhibiting cyclin-dependent kinase 2 (CDK2)/cyclin E and cyclin A complexes, controlled the initiation and progress of centrosome duplication . We transfected p21 Waf1, p27 Kip1 or p21 Waf1- p27 Kip1 genes into MCF-7 cells by lipofection to explore the effect of the genes on centrosome duplication and proliferation of breast cancer cell. The result shows that the cell growth was obviously inhibited after being transfected, resulting in an accumulation of cells in G1 and the proportion of cells which contained abnormal centrosomes was obviously decreased. Comparing with p21 Waf1or p27 Kip1, the effects of p21Waf1- p27 Kip1 genes are more significative. These results suggest that p21Waf1 and p27Kip1 genes could inhibit the growth of human breast cancer cells and reverse abnormal duplication of centrosomes. p21Waf1 and p27Kip1 cooperate to regulate centrosome duplication and cell cycle progress, indicating p21 Waf1- p27 Kip1 combined gene might be potential therapeutic agents of breast cancer which reveals suppressed p21Waf1 and p27Kip1 expression.
Highlights
The centrosome is the major microtubule organizing center during interphase and mitosis in most animal and human cells [1]
We decided to test whether re-introduction of p21Waf1 gene into MCF-7 can induce cell cycle arrest or restore the normal centrosome duplication cycle
Studies of cultured cells and tumor tissues have shown that tumorgenesis associated with suppressed p21Waf1 and p27Kip1 is primarily attributed to the deregulated centrosome duplication cycle and the consequential centrosome hyperamplification
Summary
The centrosome is the major microtubule organizing center during interphase and mitosis in most animal and human cells [1]. During mitosis, duplicated centrosomes direct formation of bipolar spindles, which is critical for accurate segregation of chromosomes and cytokinesis [3]. The centrosome duplicates once every cell cycle, which starts during the G1-S transition, coincident with the onset of DNA replication. Recent studies have shown that centrosome hyperamplification is commonly observed, and is the major contributing factor for chromosome instability in human tumors [4,5,6,7]. A significant reduction of p21Waf and p27Kip expression, which occurs at a high frequency in human cancer [8,9,10,11,12], strongly correlates with the occurrence of centrosome hyperamplification.
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