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SMAR1 Forms a Ternary Complex with p53-MDM2 and Negatively Regulates p53-mediated Transcription

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Title SMAR1 Forms a Ternary Complex with p53-MDM2 and
Negatively Regulates p53-mediated Transcription
 
Creator Pavithra, Lakshminarasimhan
Mukherjee, Srijata
Sreenath, Kadreppa
Kar, Sanchari
Sakaguchi, Kazuyasu
Roy, Siddhartha
Chattopadhyay, Samit
 
Subject Structural Biology & Bioinformatics
 
Description The intra-cellular level of tumor suppressor protein p53 is tightly controlled
by an autoregulatory feedback loop between the protein and its negative
regulator MDM2. The role of MDM2 in down-regulating the p53 response
in unstressed conditions and in the post-stress recovery phase is well
documented. However, interplay between the N-terminal phosphorylations
and C-terminal acetylations of p53 in this context remains unclear. Here, we
show that an MAR binding protein SMAR1 interacts with MDM2 and the
Ser15 phosphorylated form of p53, forming a ternary complex in the post
stress-recovery phase. This triple complex formation between p53, MDM2
and SMAR1 results in recruitment of HDAC1 to deacetylate p53. The
deacetylated p53 binds poorly to the target promoter (p21), which results in
switching off the p53 response, essential for re-entry into the cell cycle.
Interestingly, the knock-down of SMAR1 using siRNA leads to a prolonged
cell-cycle arrest in the post stress recovery phase due to ablation of p53–
MDM2–HDAC1 interaction. Thus, the results presented here for the first
time highlight the role of SMAR1 in masking the active phosphorylation site
of p53, enabling the deacetylation of p53 by HDAC1–MDM2 complex,
thereby regulating the p53 transcriptional response during stress rescue.
 
Publisher Elsevier
 
Date 2009
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1369/1/JOURNAL_OF_MOLECULAR_BIOLOGY___388(_4)_691%2D702;2009[71].pdf
Pavithra, Lakshminarasimhan and Mukherjee, Srijata and Sreenath, Kadreppa and Kar, Sanchari and Sakaguchi, Kazuyasu and Roy, Siddhartha and Chattopadhyay, Samit (2009) SMAR1 Forms a Ternary Complex with p53-MDM2 and Negatively Regulates p53-mediated Transcription. Journal of Molecular Biology, 388 (4). pp. 691-702.
 
Relation http://dx.doi.org/10.1016/j.jmb.2009.03.033
http://www.eprints.iicb.res.in/1369/