Negative regulation of BMP/Smad signaling by Tob in osteoblasts.
Bone morphogenetic protein (BMP) controls osteoblast proliferation and differentiation through Smad proteins. Here we show that Tob, a member of the emerging family of antiproliferative proteins, is a negative regulator of BMP/Smad signaling in osteoblasts. Mice carrying a targeted deletion of the tob gene have a greater bone mass resulting from increased numbers of osteoblasts. Orthotopic bone formation in response to BMP2 is elevated in tob-deficient mice. Overproduction of Tob represses BMP2-induced, Smad-mediated transcriptional activation. Finally, Tob associates with receptor-regulated Smads (Smad1, 5, and 8) and colocalizes with these Smads in the nuclear bodies upon BMP2 stimulation. The results indicate that Tob negatively regulates osteoblast proliferation and differentiation by suppressing the activity of the receptor-regulated Smad proteins.
Yoshida
Y
Y
Department of Oncology, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Tanaka
S
S
Umemori
H
H
Minowa
O
O
Usui
M
M
Ikematsu
N
N
Hosoda
E
E
Imamura
T
T
Kuno
J
J
Yamashita
T
T
Miyazono
K
K
Noda
M
M
Noda
T
T
Yamamoto
T
T
D000483:Alleles; D000818:Animals; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D016723:Bone Remodeling / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D048429:Cell Size / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D018095:Germ-Line Mutation / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012886:Skull / Q000166:cytology; D051785:Smad Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D051904:Smad8 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology; D016212:Transforming Growth Factor beta
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D010750:Phosphoproteins; C107514:SMAD9 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; C490903:Tob1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta