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.
Highlights
Nutlin-3 is the most well-characterized mdm2/p53-binding antagonist
Contrary to our initial expectations from experiments performed by long-term treatment of cells with Trichostatin A (TSA) in other labs, our results clearly showed that short-term treatment with this histone deacetylase (HDAC) inhibitor reduced the expression of p53 transcription factor function
We propose a series of explanations for the observed effects of the short-term cotreatment with TSA and Nutlin-3 on the expression of hdm[2], p21 and pig[3]
Summary
Nutlin-3 is the most well-characterized mdm2/p53-binding antagonist. We have shown that following the removal of Nutlin-3 from cell cultures, p53 protein disappears within 30 min, while mdm[2] levels remain constant for at least 3 h.4. These results suggest that achieving a cytotoxic response following p53 reactivation may be difficult with mdm2/p53-binding antagonists. TSA has been shown to reduce p53 expression by decreasing p53 promoter activity or even destabilization of P53 mRNA.[5,6] TSA and other HDAC inhibitors, including SAHA, do increase the expression of p21. We present the data obtained using a combination of Nutlin-3 and TSA in different cell lines
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
