Incompatible effects of p53 and HDAC inhibition on p21 expression and cell cycle progression.

Abstract:

:Nutlin-3 selectively activates p53 by inhibiting the interaction of this tumor suppressor with its negative regulator murine double minute 2 (mdm2), while trichostatin A (TSA) is one of the most potent histone deacetylase (HDAC) inhibitors currently available. As both Nutlin-3 and TSA increase the levels of the cell cycle inhibitor p21(cip1/waf1) in cells, we investigated whether a combination of these compounds would further augment p21 levels. Contrary to expectations, we found that short-term exposure to Nutlin-3 and TSA in combination did not have an additive effect on p21 expression. Instead, we observed that activation of p53 prevented the ability of TSA to increase p21 levels. Furthermore, TSA inhibited Nutlin-3-induced expression of p53-dependent mRNAs including P21. This negative effect of TSA on Nutlin-3 was significantly less pronounced in the case of hdm2, another p53 downstream target. Aside from suggesting a model to explain these incompatible effects of Nutlin-3 and TSA, we discuss the implications of our findings in cancer therapy and cell reprogramming.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Sachweh MC,Drummond CJ,Higgins M,Campbell J,Laín S

doi

10.1038/cddis.2013.61

subject

Has Abstract

pub_date

2013-03-07 00:00:00

pages

e533

issn

2041-4889

pii

cddis201361

journal_volume

4

pub_type

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