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SMAR1 Regulates Free Radical Stress Through Modulation of AKR1a4 Enzyme Activity

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Title SMAR1 Regulates Free Radical Stress Through Modulation of AKR1a4 Enzyme Activity
 
Creator Singh, Sandeep
Sreenath, Kadreppa
Pavithra, Lakshminarasimhan
Roy, Siddhartha
Chattopadhyay, Samit
 
Subject Structural Biology & Bioinformatics
 
Description Tumor suppressor SMAR1 is known to be involved in regulation of cell cycle and apoptotic genes transcription.
It also directly interacts and stabilizes p53 through phosphorylation at serine-15 residue.
Although the functions of SMAR1 are mainly restricted to the nucleus, we report its novel function with
the cytoplasm. We show that SMAR1 directly interacts and inhibits AKR1a4 enzyme activity. Interestingly,
AKR1a4 enzyme activity is elevated in higher grades of breast cancer where SMAR1 expression is
drastically downregulated. Higher AKR1a4 activity protects the cancer cells from anticancer drugs and
free radical stress. Through increased metabolism, ARK1a4 helps fulfilling higher energy needs required
by cancer cell. The present study delineates yet another facet of tumor suppressor activity of SMAR1 in the
cytoplasm. We also depict that upon stress, ATM kinase leads to dissociation of SMAR1–AKR1a4 complex
through nuclear translocation of SMAR1 causing elevated AKR1a4 activity. Nuclear SMAR1 causes cell
cycle arrest giving ample time for DNA damage repair, while AKR1a4 scavenges the excess free radicals
which may further cause DNA damage. Thus, we propose a novel mechanism of regulation of oxidative
stress by ATM through modulation of SMAR1–AKR1a4 complex. Further, we show that a small peptide
derived from SMAR1 induces free radical stress by inhibiting AKR1a4 enzyme activity, which can be a
potential anticancer therapeutic agent.
 
Date 2010
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/1003/1/32_ijbc_2010.pdf
Singh, Sandeep and Sreenath, Kadreppa and Pavithra, Lakshminarasimhan and Roy, Siddhartha and Chattopadhyay, Samit (2010) SMAR1 Regulates Free Radical Stress Through Modulation of AKR1a4 Enzyme Activity. The International Journal of Biochemistry, 42 (7). pp. 1105-1114.
 
Relation http://dx.doi.org/10.1016/j.biocel.2010.01.022
http://www.eprints.iicb.res.in/1003/