Stabilization of XIAP mRNA through the RNA binding protein HuR regulated by cellular polyamines.
The X chromosome-linked inhibitor of apoptosis protein (XIAP) is the most potent intrinsic caspase inhibitor and plays an important role in the maintenance of intestinal epithelial integrity. The RNA binding protein, HuR, regulates the stability and translation of many target transcripts. Here, we report that HuR associated with both the 3'-untranslated region and coding sequence of the mRNA encoding XIAP, stabilized the XIAP transcript and elevated its expression in intestinal epithelial cells. Ectopic HuR overexpression or elevated cytoplasmic levels of endogenous HuR by decreasing cellular polyamines increased [HuR/XIAP mRNA] complexes, in turn promoting XIAP mRNA stability and increasing XIAP protein abundance. Conversely, HuR silencing in normal and polyamine-deficient cells rendered the XIAP mRNA unstable, thus reducing the steady state levels of XIAP. Inhibition of XIAP expression by XIAP silencing or by HuR silencing reversed the resistance of polyamine-deficient cells to apoptosis. Our findings demonstrate that HuR regulates XIAP expression by stabilizing its mRNA and implicates HuR-mediated XIAP in the control of intestinal epithelial apoptosis.
Zhang
Xian
X
Cell Biology Group, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21224, USA.
Zou
Tongtong
T
Rao
Jaladanki N
JN
Liu
Lan
L
Xiao
Lan
L
Wang
Peng-Yuan
PY
Cui
Yu-Hong
YH
Gorospe
Myriam
M
Wang
Jian-Ying
JY
D020413:3' Untranslated Regions; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D008969:Molecular Sequence Data; D011073:Polyamines / Q000378:metabolism*; D020871:RNA Stability; D012333:RNA, Messenger / Q000737:chemistry / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism
D020413:3' Untranslated Regions; D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D011073:Polyamines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein