Fibroblast Growth Factor 21 Promotes C2C12 Cells Myogenic Differentiation by Enhancing Cell Cycle Exit

Fibroblast growth factor 21 (FGF21), a secretion protein, functions as a pivotal regulator of energy metabolism and is being considered as a therapeutic candidate in metabolic syndromes. However, the roles of FGF21 in myogenic differentiation and cell cycle remain obscure. In this study, we investigated the function of FGF21 in myogenesis and cell cycle exit using C2C12 cell line. Our data showed that the expression of myogenic genes as well as cell cycle exit genes was increased after FGF21 overexpression, and FGF21 overexpression induces cell cycle arrest. Moreover, cell cycle genes were decreased in FGF21 overexpression cells while they were increased in FGF21 knockdown cells. Further, FGF21/P53/p21/Cyclin-CDK has been suggested as the key pathway for cell cycle exit mediated by FGF21 in C2C12 cells. Also, we deduce that FGF21 promotes the initiation of myogenic differentiation mainly through enhancing cell cycle exit of C2C12 cells. Taken together, our results demonstrated that FGF21 promotes cell cycle exit and enhances myogenic differentiation of C2C12 cells. This study provided new evidence that FGF21 promotes myogenic differentiation, which could be useful for better understanding the roles of FGF21 in myogenesis.

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Activation of p107 by Fibroblast Growth Factor, Which Is Essential for Chondrocyte Cell Cycle Exit, Is Mediated by the Protein Phosphatase 2A/B55α Holoenzyme

Molecular and Cellular Biology ◽

10.1128/mcb.00082-13 ◽

2013 ◽

Vol 33 (16) ◽

pp. 3330-3342 ◽

Cited By ~ 13

Author(s):

Alison Kurimchak ◽

Dale S. Haines ◽

Judit Garriga ◽

Shufang Wu ◽

Francesco De Luca ◽

...

Keyword(s):

Cell Cycle ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Protein Phosphatase ◽

Protein Phosphatase 2A ◽

Fibroblast Growth ◽

Cell Cycle Exit ◽

Phosphorylation State ◽

Rapid Accumulation ◽

Phosphatase 2A

The phosphorylation state of pocket proteins during the cell cycle is determined at least in part by an equilibrium between inducible cyclin-dependent kinases (CDKs) and serine/threonine protein phosphatase 2A (PP2A). Two trimeric holoenzymes consisting of the core PP2A catalytic/scaffold dimer and either the B55α or PR70 regulatory subunit have been implicated in the activation of p107/p130 and pRB, respectively. While the phosphorylation state of p107 is very sensitive to forced changes of B55α levels in human cell lines, regulation of p107 in response to physiological modulation of PP2A/B55α has not been elucidated. Here we show that fibroblast growth factor 1 (FGF1), which induces maturation and cell cycle exit in chondrocytes, triggers rapid accumulation of p107-PP2A/B55α complexes coinciding with p107 dephosphorylation. Reciprocal solution-based mass spectrometric analysis identified the PP2A/B55α complex as a major component in p107 complexes, which also contain E2F/DPs, DREAM subunits, and/or cyclin/CDK complexes. Of note, p107 is one of the preferred partners of B55α, which also associates with pRB in RCS cells. FGF1-induced dephosphorylation of p107 results in its rapid accumulation in the nucleus and formation of larger complexes containing p107 and enhances its interaction with E2F4 and other p107 partners. Consistent with a key role of B55α in the rapid activation of p107 in chondrocytes, limited ectopic expression of B55α results in marked dephosphorylation of p107 while B55α knockdown results in hyperphosphorylation. More importantly, knockdown of B55α dramatically delays FGF1-induced dephosphorylation of p107 and slows down cell cycle exit. Moreover, dephosphorylation of p107 in response to FGF1 treatment results in early recruitment of p107 to theMYCpromoter, an FGF1/E2F-regulated gene. Our results suggest a model in which FGF1 mediates rapid dephosphorylation and activation of p107 independently of the CDK activities that maintain p130 and pRB hyperphosphorylation for several hours after p107 dephosphorylation in maturing chondrocytes.

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Control of myogenic differentiation by fibroblast growth factor is mediated by position in the G1 phase of the cell cycle.

The Journal of Cell Biology ◽

10.1083/jcb.101.6.2194 ◽

1985 ◽

Vol 101 (6) ◽

pp. 2194-2198 ◽

Cited By ~ 63

Author(s):

B Lathrop ◽

K Thomas ◽

L Glaser

Keyword(s):

Cell Cycle ◽

Growth Factor ◽

Fibroblast Growth Factor ◽

Myogenic Differentiation ◽

G1 Phase ◽

Primary Control ◽

Fibroblast Growth ◽

Restriction Point ◽

Polypeptide Growth Factors ◽

Specific Proteins

We have used the expression of the muscle form of creatine phosphokinase (M-CPK) to assay myogenic differentiation in the cloned muscle cell line BC3Hl. BC3Hl cells express M-CPK when arrested in the G0 portion of the cell cycle. Addition of the anionic form of brain fibroblast growth factor (B-FGF) rapidly represses synthesis of M-CPK with a half-time of 7 h. Even though B-FGF is not mitogenic for the cells, it causes quiescent BC3Hl cells to exit from the G0 portion of the cell cycle, and to accumulate at a new restriction point approximately 4 to 6 h in the G1 portion of the cell cycle. The repression of M-CPK synthesis by B-FGF is reversible upon removal of B-FGF, and cells which have re-initiated expression of M-CPK have also returned to the G0 portion of the cell cycle. The primary control of M-CPK expression by B-FGF appears to be at the level of gene transcription. We conclude that arrest of cells at G0 but not at other positions in the G1 phase of the cell cycle provides permissive conditions for the expression of muscle-specific proteins, and that defined polypeptide growth factors, in this case B-FGF, are important in the control of the expression of muscle-specific proteins.

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