A microRNA-21 surge facilitates rapid cyclin D1 translation and cell cycle progression in mouse liver regeneration.
MicroRNA-21 (miR-21) is thought to be an oncomir because it promotes cancer cell proliferation, migration, and survival. miR-21 is also expressed in normal cells, but its physiological role is poorly understood. Recently, it has been found that miR-21 expression is rapidly induced in rodent hepatocytes during liver regeneration after two-thirds partial hepatectomy (2/3 PH). Here, we investigated the function of miR-21 in regenerating mouse hepatocytes by inhibiting it with an antisense oligonucleotide. To maintain normal hepatocyte viability and function, we antagonized the miR-21 surge induced by 2/3 PH while preserving baseline expression. We found that knockdown of miR-21 impaired progression of hepatocytes into S phase of the cell cycle, mainly through a decrease in levels of cyclin D1 protein, but not Ccnd1 mRNA. Mechanistically, we discovered that increased miR-21 expression facilitated cyclin D1 translation in the early phase of liver regeneration by relieving Akt1/mTOR complex 1 signaling (and thus eIF-4F-mediated translation initiation) from suppression by Rhob. Our findings reveal that miR-21 enables rapid hepatocyte proliferation during liver regeneration by accelerating cyclin D1 translation.
Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, UCSF, San Francisco, California 94143, USA.
Raymond
R
Ng
Guisheng
G
Song
Garrett R
GR
Roll
Niels M
NM
Frandsen
Holger
H
Willenbring
D000818:Animals; D002453:Cell Cycle; D002455:Cell Division; D019938:Cyclin D1 / Q000096:biosynthesis*; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000378:metabolism*; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000378:metabolism
C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D012333:RNA, Messenger; D019938:Cyclin D1; D020743:rhoB GTP-Binding Protein