Themicrophthalmiatranscription factor (MITF) contains two N-terminal domains required for transactivation of osteoclast target promoters and rescue ofmimutant osteoclasts

Abstract

The microphthalmia transcription factor (MITF) regulates gene expression during differentiation of several distinct cell types, including osteoclasts. A structure/function analysis was performed to determine whether transcription activation domains were important for MITF action in osteoclasts. In addition to a previously characterized acidic activation necessary for melanocyte differentiation, the analysis defined a second potential activation domain located between amino acids 140 and 185. This second domain is required for MITF transactivation of two probable targets, the E-cadherin promoter and the tartrate-resistant acid phosphatase promoter, in transient transfection assays. An intact MITF gene rescued differentiation when introduced into osteoclasts derived from mi/mi mice using a retrovirus vector. In parallel experiments, an MITF gene lacking the acidic-activation domain rescued differentiation twofold less efficiently than wild type, and a gene lacking the region between amino acid residues 140 and 185 rescued differentiation tenfold less efficiently than wild type. The results indicate that the N-terminal region of MITF is necessary for activation of gene expression in osteoclasts and provides one mechanism by which this factor regulates distinct target genes in different cell types.

Extracellular Signal-Regulated Kinases Play Essential but Contrasting Roles in Osteoclast Differentiation

“…The p38 MAPK pathway plays a key role in the regulation of OC formation and maturation, and thus, in bone resorption and remodeling [3,68,104,105]. p38 MAPK stimulates the downstream activation of the transcriptional regulator microphthalmia-associated transcription factor (MITF), which controls the expression of the genes encoding TRAP and CTSK [3,106]. The p38 MAPK contains four isoforms of p38 (α, β, γ, and δ) and p38α is the most expressed isoform in OCs that plays a key role in OC differentiation and bone resorption [107].…”