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PMID:19008232

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Citation

Zhang, H and Stavnezer, E (2009) Ski regulates muscle terminal differentiation by transcriptional activation of Myog in a complex with Six1 and Eya3. J. Biol. Chem. 284:2867-79

Abstract

Overexpression of the Ski pro-oncogene has been shown to induce myogenesis in non-muscle cells, to promote muscle hypertrophy in postnatal mice, and to activate transcription of muscle-specific genes. However, the precise role of Ski in muscle cell differentiation and its underlying molecular mechanism are not fully understood. To elucidate the involvement of Ski in muscle terminal differentiation, two retroviral systems were used to achieve conditional overexpression or knockdown of Ski in satellite cell-derived C2C12 myoblasts. We found that enforced expression of Ski promoted differentiation, whereas loss of Ski severely impaired it. Compromised terminal differentiation in the absence of Ski was likely because of the failure to induce myogenin (Myog) and p21 despite normal expression of MyoD. Chromatin immunoprecipitation and transcriptional reporter experiments showed that Ski occupied the endogenous Myog regulatory region and activated transcription from the Myog regulatory region upon differentiation. Transactivation of Myog was largely dependent on a MEF3 site bound by Six1, not on the binding site of MyoD or MEF2. Activation of the MEF3 site required direct interaction of Ski with Six1 and Eya3 mediated by the evolutionarily conserved Dachshund homology domain of Ski. Our results indicate that Ski is necessary for muscle terminal differentiation and that it exerts this role, at least in part, through its association with Six1 and Eya3 to regulate the Myog transcription.

Links

PubMed PMC2631951 Online version:10.1074/jbc.M807526200

Keywords

Animals; Base Sequence; Blotting, Western; Cell Differentiation/physiology; Cell Line; Chromatin Immunoprecipitation; DNA Primers; DNA-Binding Proteins/metabolism; DNA-Binding Proteins/physiology; Gene Knockdown Techniques; Homeodomain Proteins/metabolism; Mice; Muscles/cytology; Mutagenesis, Site-Directed; Myogenin/genetics; Myogenin/metabolism; Polymerase Chain Reaction; Protein Binding; Proto-Oncogene Proteins/physiology; Transcriptional Activation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SKI

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P97480

F

Seeded From UniProt

complete

HUMAN:SKI

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q62231

F

Seeded From UniProt

complete

HUMAN:SKI

involved_in

GO:0014902: myotube differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:EYA3

enables

GO:0003682: chromatin binding

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:102780
MGI:MGI:98310

F

Seeded From UniProt

complete

MOUSE:EYA3

part_of

GO:0005667: transcription regulator complex

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q60698
PR:Q62231

C

Seeded From UniProt

complete

MOUSE:EYA3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12755

F

Seeded From UniProt

complete

MOUSE:SKI

acts_upstream_of_or_within

GO:0014902: myotube differentiation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:102780
MGI:MGI:109339

P

Seeded From UniProt

complete

MOUSE:SKI

enables

GO:0003682: chromatin binding

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:102780
MGI:MGI:109339

F

  • has_input:(MGI:MGI:97276)

Seeded From UniProt

complete

MOUSE:SKI

part_of

GO:0005667: transcription regulator complex

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q62231
UniProtKB:P97480

C

Seeded From UniProt

complete

MOUSE:SKI

acts_upstream_of_or_within

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:102780
MGI:MGI:109339

P

  • has_input:(MGI:MGI:97276)

Seeded From UniProt

complete

MOUSE:SIX1

enables

GO:0003682: chromatin binding

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109339
MGI:MGI:98310

F

Seeded From UniProt

complete

MOUSE:SIX1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12755

F

Seeded From UniProt

complete


See also

References

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