Post-mitotic role of nucleostemin as a promoter of skeletal muscle cell differentiation.
Nucleostemin (NS) is a nucleolar protein abundantly expressed in a variety of proliferating cells and undifferentiated cells. Its known functions include cell cycle regulation and the control of pre-rRNA processing. It also has been proposed that NS has an additional role in undifferentiated cells due to its downregulation during stem cell differentiation and its upregulation during tissue regeneration. Here, however, we demonstrate that skeletal muscle cell differentiation has a unique expression profile of NS in that it is continuously expressed during differentiation. NS was expressed at similar levels in non-proliferating muscle stem cells (satellite cells), rapidly proliferating precursor cells (myoblasts) and post-mitotic terminally differentiated cells (myotubes and myofibers). The sustained expression of NS during terminal differentiation is necessary to support increased protein synthesis during this process. Downregulation of NS inhibited differentiation of myoblasts to myotubes, accompanied by striking downregulation of key myogenic transcription factors, such as myogenin and MyoD. In contrast, upregulation of NS inhibited proliferation and promoted muscle differentiation in a p53-dependent manner. Our findings provide evidence that NS has an unexpected role in post-mitotic terminal differentiation. Importantly, these findings also indicate that, contrary to suggestions in the literature, the expression of NS cannot always be used as a reliable indicator for undifferentiated cells or proliferating cells.
Hirai
Hiroyuki
H
Stem Cell Institute, University of Minnesota, Room 2-216, MTRF, 2001 6th St SE, Minneapolis, MN 55455, USA.
Romanova
Liudmila
L
Kellner
Steven
S
Verma
Mayank
M
Rayner
Samuel
S
Asakura
Atsushi
A
Kikyo
Nobuaki
N
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics*; D019204:GTP-Binding Proteins; D055785:Gene Knockdown Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis; D024510:Muscle Development / Q000235:genetics*; D018482:Muscle, Skeletal / Q000166:cytology*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D016601:RNA-Binding Proteins; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D002352:Carrier Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C470311:nucleostemin protein, mouse; D019204:GTP-Binding Proteins