NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1 [In Process Citation]

  • Guttridge D
  • Albanese C
  • Reuther J
  • et al.
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Abstract

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.

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Guttridge, D. C., Albanese, C., Reuther, J. Y., Pestell, R. G., & Baldwin  Jr., A. S. (1999). NF-kappaB controls cell growth and differentiation through transcriptional regulation of cyclin D1 [In Process Citation]. Mol Cell Biol, 19(8), 5785–5799. Retrieved from http://www.ncbi.nlm.nih.gov/cgi-bin/Entrez/referer?http://mcb.asm.org/cgi/content/full/19/8/5785

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