Essential role of the RNA-binding protein HuR in progenitor cell survival in mice.
The RNA-binding protein HuR (also known as ELAV1) binds to the 3'-untranslated region of mRNAs and regulates transcript stability and translation. However, the in vivo functions of HuR are not well understood. Here, we report that murine HuR is essential for life; postnatal global deletion of Elavl1 induced atrophy of hematopoietic organs, extensive loss of intestinal villi, obstructive enterocolitis, and lethality within 10 days. Upon Elavl1 deletion, progenitor cells in the BM, thymus, and intestine underwent apoptosis, whereas quiescent stem cells and differentiated cells were unaffected. The survival defect of hematopoietic progenitor cells was cell intrinsic, as transplant of Elavl1-/- BM led to compromised hematopoietic reconstitution but did not cause lethality. Expression of p53 and its downstream effectors critical for cell death were induced in progenitor cells as HuR levels declined. In mouse embryonic fibroblasts, HuR bound to and stabilized the mRNA for Mdm2, a critical negative regulator of p53. Furthermore, cell survival was restored by expression of Mdm2 in Elavl1-/- cells, suggesting that HuR keeps p53 levels in check in progenitor cells and thereby promotes cell survival. This regulation of cell stress response by HuR in progenitor cells, which we believe to be novel, could potentially be exploited in cytotoxic anticancer therapies as well as stem cell transplant therapy.
Ghosh
Mallika
M
Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.
Aguila
Hector Leonardo
HL
Michaud
Jason
J
Ai
Youxi
Y
Wu
Ming-Tao
MT
Hemmes
Annabrita
A
Ristimaki
Ari
A
Guo
Caiying
C
Furneaux
Henry
H
Hla
Timothy
T
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis; D002454:Cell Differentiation; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; D005260:Female; D041981:Gastrointestinal Tract / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011836:Radiation Tolerance; D013629:Tamoxifen / Q000633:toxicity; D018183:Transplantation Chimera; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000954:Antigens, Surface; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2