Neuromuscular abundance of RB1CC1 contributes to the non-proliferating enlarged cell phenotype through both RB1 maintenance and TSC1 degradation.
RB1-inducible coiled-coil 1 (RB1CC1) is a novel tumor suppressor implicated in the regulation of RB1 expression. It is abundant in post-mitotic neuromuscular cells, which are matured and enlarged, but scarce in smaller leukocytes, indicating an association between RB1CC1 status and cell size. To clarify whether RB1CC1 is involved in cell size control, we investigated the contribution of RB1CC1 to the TSC-mTOR pathway, which plays an important role in the control through translational regulation. RNAi-mediated knockdown of RB1CC1 reduced the activation of mTOR and S6K as well as the size of HEK293 and C2C12 cells. Such knockdown also suppressed RB1 expression and the population of G1-phase cells. Exogenous expression of RB1CC1 maintained S6K activity and cell size, and decreased TSC1/hamartin contents under nutritionally starved conditions, which usually inhibit the mTOR-S6K pathway. Furthermore, RB1CC1 interfered with and degraded TSC1 through the ubiquitin-proteasomal pathway. A lentiviral RNAi for RB1CC1 reduced the size of mouse leg muscles. These findings suggest that RB1CC1 is required to maintain both RB1 expression and mTOR activity. The activity of mTOR was supported by RB1CC1 through TSC1 degradation. RB1CC1 preserved cell size without cell cycle progression especially in neuromuscular tissues, and the abundance contributed to the non-proliferating enlarged cell phenotype.
Chano
Tokuhiro
T
Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Shiga 520-2192, Japan. chano@belle.shiga-med.ac.jp
Saji
Masashi
M
Inoue
Hirokazu
H
Minami
Kahori
K
Kobayashi
Toshiyuki
T
Hino
Okio
O
Okabe
Hidetoshi
H
D000818:Animals; D000071183:Autophagy-Related Proteins; D002453:Cell Cycle; D049108:Cell Enlargement; D015536:Down-Regulation; D015870:Gene Expression; D006614:Hindlimb / Q000254:growth & development; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D009133:Muscular Atrophy / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011489:Protein Denaturation / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D016160:Retinoblastoma Protein / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D013217:Starvation / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D000071183:Autophagy-Related Proteins; C407704:RB1CC1 protein, human; D016160:Retinoblastoma Protein; C000624650:TSC1 protein, human; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D011505:Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex