Negative regulation of BMP/Smad signaling by Tob in osteoblasts

Y Yoshida; S Tanaka; H Umemori; O Minowa; M Usui; N Ikematsu; E Hosoda; T Imamura; J Kuno; T Yamashita; K Miyazono; M Noda; T Noda; T Yamamoto

doi:10.1016/s0092-8674(00)00211-7

Negative regulation of BMP/Smad signaling by Tob in osteoblasts

Cell. 2000 Dec 22;103(7):1085-97. doi: 10.1016/s0092-8674(00)00211-7.

Authors

Y Yoshida¹, S Tanaka, H Umemori, O Minowa, M Usui, N Ikematsu, E Hosoda, T Imamura, J Kuno, T Yamashita, K Miyazono, M Noda, T Noda, T Yamamoto

Affiliation

¹ Department of Oncology, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

PMID: 11163184
DOI: 10.1016/s0092-8674(00)00211-7

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Bone Morphogenetic Protein 2
Bone Morphogenetic Protein 7
Bone Morphogenetic Proteins / metabolism*
Bone Remodeling / physiology
Carrier Proteins / genetics*
Carrier Proteins / metabolism*
Cell Differentiation / physiology
Cell Division / physiology
Cell Size / physiology
DNA-Binding Proteins / metabolism*
Gene Expression / physiology
Germ-Line Mutation / physiology
Intracellular Signaling Peptides and Proteins
Ligands
Mice
Mice, Inbred C57BL
Mice, Knockout
Osteoblasts / cytology
Osteoblasts / physiology*
Phosphoproteins / metabolism
Signal Transduction / physiology*
Skull / cytology
Smad Proteins
Smad1 Protein
Smad5 Protein
Smad8 Protein
Trans-Activators / metabolism*
Transcription, Genetic / physiology
Transforming Growth Factor beta*

Substances

Bmp2 protein, mouse
Bone Morphogenetic Protein 2
Bone Morphogenetic Protein 7
Bone Morphogenetic Proteins
Carrier Proteins
DNA-Binding Proteins
Intracellular Signaling Peptides and Proteins
Ligands
Phosphoproteins
SMAD9 protein, human
Smad Proteins
Smad1 Protein
Smad1 protein, mouse
Smad5 Protein
Smad5 protein, mouse
Smad8 Protein
Smad9 protein, mouse
Tob1 protein, mouse
Trans-Activators
Transforming Growth Factor beta