NF-κB Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1

TLDR

Accumulating evidence implicates NF‑κB as a positive mediator of cell growth, yet the underlying mechanisms remain largely unknown. The study uses skeletal muscle differentiation and diploid fibroblast models to investigate how NF‑κB regulates cell growth and differentiation. NF‑κB activates cyclin D1 transcription by directly binding multiple sites in its promoter. NF‑κB inhibits myogenic differentiation, promotes proliferation and G1‑S progression by up‑regulating cyclin D1, thereby linking NF‑κB to early cell‑cycle control of growth and differentiation.

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.