JunB Is Involved in the Inhibition of Myogenic Differentiation by Bone Morphogenetic Protein-2

Abstract

Bone morphogenetic proteins (BMPs) constitute a family of multifunctional growth and differentiation factors structurally related to transforming growth factor-␤. BMPs were first identified by their osteoinductive effects, inducing ectopic bone formation when implanted in skeletal muscle, and have an important role as regulators of skeletal development in vivo. In vitro, BMP-2 is able to transdifferentiate myogenic C2C12 cells into the osteoblastic phenotype. In this report, we show that the osteoinductive effects of BMP-2 in C2C12 cells are mediated by bone morphogenetic protein receptor type-IA in combination with both activin receptor type II and bone morphogenetic protein receptor type II. We also analyzed the expression levels of nuclear protooncogenes to understand early transcriptional events induced by BMP-2. We show that junB is an immediate early gene induced by BMP-2 and transforming growth factor-␤. BMP-2 induces transcriptional activation of JunB expression as early as 30 min after ligand addition, reaching maximal levels after 90 min. Increase of JunB mRNA correlates with a higher AP-1 binding activity. Furthermore, ectopic overexpression of JunB is sufficient to inhibit expression of myoblast differentiation markers in C2C12 cells. These data, taken together, show the involvement of JunB in the early steps of inhibition of myogenic differentiation induced by transforming growth factor-␤ family members.

The mammalian Jun proteins: redundancy and specificity

“…While c-Jun expression is completely inhibited, JunB expression is induced in response to PKA (cAMP-dependent Protein Kinase) activation . The negative e ect of JunB on cell proliferation is also consistent with its induction by inhibitors of cell growth such as TGFb (Transforming Growth Factor b) or inhibitors of myogenic di erentiation, like BMP2 (bone Morphogenetic Protein), which alters cell lineage from the myogenic to the osteogenic lineage (Chalaux et al, 1998). Smad proteins were identi®ed as downstream e ectors of the TGFb-dependent signal transduction pathway.…”

Growth and differentiation factor-11 is developmentally regulated in skeletal muscle and inhibits myoblast differentiation

“…However, we must acknowledge that differences between the downstream signalling of myostatin and GDF-11 are likely and are unclear at present. It is also equally likely that other TGF-β ligands such as activin A, BMP-2 or TGF-β1 play a role in regulating skeletal myogenesis as it has been suggested by others [25][26][27].…”

Profiling the molecular difference between Patched- and p53-dependent rhabdomyosarcoma

“…These genes were also strongly expressed in C2C12 cells, but displayed only low levels in SM tissue. By compiling sets of genes that vary significantly in their mean relative expression between the two RMS subtypes (Tables 2 and 3), we detected several genes previously associated with rhabdomyosarcomagenesis or myogenic differentiation, namely Fos (Fleischmann et al, 2003), myogenic differentiation 1 (MyoD1) (Kablar et al, 2003), Junb (Chalaux et al, 1998), follistatin (Amthor et al, 2002;Armand et al, 2003), heparin binding epidermal growth factor-like growth factor (Chen et al, 1995), matrix metalloproteinase 9 (Kherif et al, 1999) and p21 cip1/waf1 (see Figure 4b). These genes generally displayed higher transcript levels in Ptch1-dependend RMS than in p53-dependend RMS (Table 2).…”