Abstract
The mechanism of suberoylanilide hydroxamic acid in cell growth inhibition involved induction of pRb-2/p130 interaction and nuclear translocation with E2F-4, followed by significant repression in E2F-1 and PCNA nuclear levels, which led to inhibition in DNA synthesis in mammary epithelial cell lines.
Highlights
Progression through the mammalian cell cycle requires that gene expression is coordinated with the activity of cell cycle control proteins
We have previously reported that the prototype Hybrid polar compounds (HPCs) was able to arrest the growth of transformed mammary (TM) 2H cells (p53 null), a highly tumorigenic mouse mammary epithelial cell line, by inhibiting G1 kinase activities, concomitant with an increase in the cyclin D2 protein level and hypophosphorylated isoforms of the three pRb pocket proteins, which led to the formation of stable cyclin D2/pRb complexes and G1 cell arrest
TM10 and TM2H cells were examined in the presence or absence of 2.5 μM SAHA for cell growth rate by [3H]-thymidine uptake, DNA synthesis by flow cytometry after cells were labeled with BrdU, G1/S cyclin-dependent kinase activities, phosphorylation levels of pRb pocket proteins, protein levels of E2F-1, PCNA and p21, pRb-2/p130 interaction, and nuclear localization with E2F-4 by western blot, immunoprecipitation and immunostaining assays
Summary
Progression through the mammalian cell cycle requires that gene expression is coordinated with the activity of cell cycle control proteins. Conclusion: A novel mechanism of SAHA mediated growth inhibition through significant increases in the formation and nuclear localization of pRb-2/p130–E2F-4 complexes, which resulted in cell growth arrest and significant repression in the levels of two key molecules, E2F-1 and PCNA, essential for DNA synthesis in two mouse mammary epithelial cell lines. These responses to SAHA were independent of the p53 status of the cell; reversibility of SAHA-mediated growth correlated with the wild type p53 status
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