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Publication : The role of p21(waf1/cip1) and p27(Kip1) in HDACi-mediated tumor cell death and cell cycle arrest in the Eμ-myc model of B-cell lymphoma.

First Author  Newbold A Year  2014
Journal  Oncogene Volume  33
Issue  47 Pages  5415-23
PubMed ID  24292681 Mgi Jnum  J:216558
Mgi Id  MGI:5608980 Doi  10.1038/onc.2013.482
Citation  Newbold A, et al. (2014) The role of p21(waf1/cip1) and p27(Kip1) in HDACi-mediated tumor cell death and cell cycle arrest in the Emu-myc model of B-cell lymphoma. Oncogene 33(47):5415-23
abstractText  Following the establishment of histone deacetylases (HDACs) as promising therapeutic targets for the reversal of aberrant epigenetic states associated with cancer, the development of HDAC inhibitors (HDACi) and their underlying mechanisms of action has been a significant area of scientific interest. HDACi induce diverse biological responses including the inhibition of cell proliferation by blocking progression through the G1 or G2/M phases of the cell cycle. As a putative tumor-suppressor protein, p21(waf1/cip1) influences cell proliferation by inhibiting the activity of cyclin-cyclin-dependent kinase (CDK) complexes at the G1/S and G2/M cell cycle checkpoints. HDACi transcriptionally activate CDKN1A, and it has been proposed that induction of p21(waf1/cip1) can determine if a cell undergoes apoptosis or cell cycle arrest following HDACi treatment. In the Emu-myc transgenic mouse model of B-cell lymphoma, knockout of cdkn1a had no effect on disease latency, indicating that p21(waf1/cip1) did not function as a tumor suppressor in this system. Although HDACi robustly induced expression of p21(waf1/cip1) in wild-type Emu-myc lymphomas, deletion of cdkn1a did not sensitize the lymphoma cells to HDACi-induced apoptosis and HDACi-induced cell cycle arrest still occurred. However, knockdown of cdkn1b in cdkn1a knockout lymphomas resulted in defective vorinostat-mediated arrest at G1/S indicating an essential role of p27(Kip1) in mediating this biological response to vorinostat. These data demonstrate that induction of cdkn1a does not regulate HDACi-mediated tumor cell apoptosis and refute the notion that p21(waf1/cip1) is an obligate mediator of HDACi-induced cell cycle arrest.
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