Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation.
Osteoclasts are bone-resorbing cells derived from haematopoietic precursors of the monocyte-macrophage lineage. Mice lacking Fos (encoding c-Fos) develop osteopetrosis due to an early differentiation block in the osteoclast lineage. c-Fos is a component of the dimeric transcription factor activator protein-1 (Ap-1), which is composed mainly of Fos (c-Fos, FosB, Fra-1 and Fra-2) and Jun proteins (c-Jun, JunB and JunD). Unlike Fra-1 (encoded by Fosl1), c-Fos contains transactivation domains required for oncogenesis and cellular transformation. The mechanism by which c-Fos exerts its specific function in osteoclast differentiation is not understood. Here we show by retroviral-gene transfer that all four Fos proteins, but not the Jun proteins, rescue the differentiation block in vitro. Structure-function analysis demonstrated that the major carboxy-terminal transactivation domains of c-Fos and FosB are dispensable and that Fra-1 (which lacks transactivation domains) has the highest rescue activity. Moreover, a transgene expressing Fra-1 rescues the osteopetrosis of c-Fos-mutant mice in vivo. The osteoclast differentiation factor Rankl (also known as TRANCE, ODF and OPGL; refs 8-11) induces transcription of Fosl1 in a c-Fos-dependent manner, thereby establishing a link between Rank signalling and the expression of Ap-1 proteins in osteoclast differentiation.
Matsuo
K
K
Research Institute of Molecular Pathology, Vienna, Austria.
Owens
J M
JM
Tonko
M
M
Elliott
C
C
Chambers
T J
TJ
Wagner
E F
EF
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D051921:Fos-Related Antigen-2; D016762:Genes, fos; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000099169:Fos-Related Antigen 1
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051921:Fos-Related Antigen-2; D008562:Membrane Glycoproteins; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors; D000099169:Fos-Related Antigen 1; C497873:Fosl2 protein, mouse; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse