NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1.
Accumulating evidence implicates the transcription factor NF-kappaB as a positive mediator of cell growth, but the molecular mechanism(s) involved in this process remains largely unknown. Here we use both a skeletal muscle differentiation model and normal diploid fibroblasts to gain insight into how NF-kappaB regulates cell growth and differentiation. Results obtained with the C2C12 myoblast cell line demonstrate that NF-kappaB functions as an inhibitor of myogenic differentiation. Myoblasts generated to lack NF-kappaB activity displayed defects in cellular proliferation and cell cycle exit upon differentiation. An analysis of cell cycle markers revealed that NF-kappaB activates cyclin D1 expression, and the results showed that this regulatory pathway is one mechanism by which NF-kappaB inhibits myogenesis. NF-kappaB regulation of cyclin D1 occurs at the transcriptional level and is mediated by direct binding of NF-kappaB to multiple sites in the cyclin D1 promoter. Using diploid fibroblasts, we demonstrate that NF-kappaB is required to induce cyclin D1 expression and pRb hyperphosphorylation and promote G(1)-to-S progression. Consistent with results obtained with the C2C12 differentiation model, we show that NF-kappaB also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1. These data therefore identify cyclin D1 as an important transcriptional target of NF-kappaB and reveal a mechanism to explain how NF-kappaB is involved in the early phases of the cell cycle to regulate cell growth and differentiation.
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7295, USA.
D C
DC
Guttridge
C
C
Albanese
J Y
JY
Reuther
R G
RG
Pestell
A S
AS
Baldwin
D016475:3T3 Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002455:Cell Division / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016384:Consensus Sequence; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D016193:G1 Phase; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D014158:Transcription, Genetic; D014162:Transfection
D016328:NF-kappa B; D011993:Recombinant Fusion Proteins; D019938:Cyclin D1