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Divergent impact of actin isoforms on cell cycle regulation.

ABSTRACT: We have shown that cytoplasmic actin isoforms play different roles in neoplastic cell transformation. ?-Cytoplasmic actin acts as a tumor suppressor, affecting epithelial differentiation, cell growth, cell invasion and tumor growth of colon and lung carcinoma cells. In contrast, ?-cytoplasmic actin enhances malignant features of tumor cells whose actin network regulation is carried out via the ?-actin isoform. The goal of this study was to describe the role of cytoplasmic actins in cell cycle regulation of breast cancer cell lines MCF-7 and MDA-MB-231. The distinct roles of each cytoplasmic actin in the cell cycle driving were observed. ?-Actin as well as ?-actin down-regulation inhibited proliferation of breast cancer cells, but only down-regulation of ?-actin induced a significant decrease in diploid cell population and accumulation of tetraploid cells. Down-regulation of ?-actin stimulated cyclin A2, B1 and D3 expression, whereas down-regulation of ?-actin reduced expression of these cyclins in both cell lines. Moreover, cyclin B1 and ?-actin were co-localized in mitotic control and ?-actin-deficient cells. In mitotic MCF-7 cells down-regulation of ?-actin caused an enrichment of prophase/metaphase population compared with control. ?-Actin down-regulation induced telophase enrichment. ERK1/2 and ?-actin co-localization and possible selective binding were revealed in MCF7 cells. ?-Actin down-regulation induced ERK1/2 activation, while ?-actin down-regulation led to reduction of p-ERK1/2. A direct interaction of ERK1/2 with ?-actin and cyclin A2 in the same protein complex was also discovered. We suggest that ?-actin down-regulation leads to decrease of cyclin A2 level, inhibits ERK1/2 signaling and deceleration of breast cancer cells proliferation.

SUBMITTER: Dugina V

PROVIDER: S-EPMC6300101 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:The p53 tumor suppressor is a sequence-specific pleiotropic transcription factor that coordinates cellular responses to DNA damage and stress, initiating cell-cycle arrest or triggering apoptosis. Although the human p53 binding site sequence (or response element [RE]) is well characterized, some genes have consensus-poor REs that are nevertheless both necessary and sufficient for transactivation by p53. Identification of new functional gene regulatory elements under these conditions is problematic, and evolutionary conservation is often employed. We evaluated the comparative genomics approach for assessing evolutionary conservation of putative binding sites by examining conservation of 83 experimentally validated human p53 REs against mouse, rat, rabbit, and dog genomes and detected pronounced conservation differences among p53 REs and p53-regulated pathways. Bona fide NRF2 (nuclear factor [erythroid-derived 2]-like 2 nuclear factor) and NFkappaB (nuclear factor of kappa light chain gene enhancer in B cells) binding sites, which direct oxidative stress and innate immunity responses, were used as controls, and both exhibited high interspecific conservation. Surprisingly, the average p53 RE was not significantly more conserved than background genomic sequence, and p53 REs in apoptosis genes as a group showed very little conservation. The common bioinformatics practice of filtering RE predictions by 80% rodent sequence identity would not only give a false positive rate of approximately 19%, but miss up to 57% of true p53 REs. Examination of interspecific DNA base substitutions as a function of position in the p53 consensus sequence reveals an unexpected excess of diversity in apoptosis-regulating REs versus cell-cycle controlling REs (rodent comparisons: p < 1.0 e-12). While some p53 REs show relatively high levels of conservation, REs in many genes such as BAX, FAS, PCNA, CASP6, SIVA1, and P53AIP1 show little if any homology to rodent sequences. This difference suggests that among mammalian species, evolutionary conservation differs among p53 REs, with some having ancient ancestry and others of more recent origin. Overall our results reveal divergent evolutionary pressure among the binding targets of p53 and emphasize that comparative genomics methods must be used judiciously and tailored to the evolutionary history of the targeted functional regulatory regions.

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Divergent impact of actin isoforms on cell cycle regulation.

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