Transforming Growth Factor-beta Stimulates Cyclin D1 Expression through Activation of beta-Catenin Signaling in Chondrocytes

Department of Orthopaedics, Center for Musculoskeletal Research, University of Rochester, New York 14642, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2006; 281(30):21296-304. DOI: 10.1074/jbc.M600514200
Source: PubMed

ABSTRACT Transforming growth factor-β (TGF-β) plays an essential role in chondrocyte maturation. It stimulates chondrocyte proliferation
but inhibits chondrocyte differentiation. In this study, we found that TGF-β rapidly induced β-catenin protein levels and
signaling in murine neonatal sternal primary chondrocytes. TGF-β-increased β-catenin induction was reproduced by overexpression
of SMAD3 and was absent in Smad3-/- chondrocytes treated with TGF-β. SMAD3 inhibited β-transducin repeat-containing protein-mediated degradation of β-catenin
and immunoprecipitated with β-catenin following TGF-β treatment. Both SMAD3 and β-catenin co-localized to the nucleus after
TGF-β treatment. Although both TGF-β and β-catenin stimulated cyclin D1 expression in chondrocytes, the effect of TGF-β was inhibited with β-catenin gene deletion or SMAD3 loss of function. These
results demonstrate that TGF-β stimulates cyclin D1 expression at least in part through activation of β-catenin signaling.

Download full-text


Available from: Tian-Fang Li, Sep 26, 2015
48 Reads
  • Source
    • "Primary sternal chondrocytes were isolated from 2- to 3-day-old Tak1f/f mice as described previously(41–43) or from E14.5 cartilage elements of the limb. All cells were seeded as follows: 1 × 106 cells per well in a six-well plate and maintained in DMEM containing 10% FBS and 1% penicillin/streptomycin. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The importance of canonical transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) signaling during cartilage and joint development is well established, but the necessity for noncanonical (SMAD-independent) signaling during these processes is largely unknown. TGF-beta activated kinase 1 (TAK1) is a MAP3K activated by TGF-beta, BMP, and other mitogen-activated protein kinase (MAPK) signaling components. We set out to define the potential role for noncanonical, TAK1-mediated signaling in cartilage and joint development via deletion of Tak1 in chondrocytes (Col2Cre;Tak1(f/f)) and the developing limb mesenchyme (Prx1Cre;Tak1(f/f)). Deletion of Tak1 in chondrocytes resulted in novel embryonic developmental cartilage defects including decreased chondrocyte proliferation, reduced proliferating chondrocyte survival, delayed onset of hypertrophy, reduced Mmp13 expression, and a failure to maintain interzone cells of the elbow joint, which were not observed previously in another Col2Cre;Tak1(f/f) model. Deletion of Tak1 in limb mesenchyme resulted in widespread joint fusions likely owing to the differentiation of interzone cells to the chondrocyte lineage. The Prx1Cre;Tak1(f/f) model also allowed us to identify novel columnar chondrocyte organization and terminal maturation defects owing to the interplay between chondrocytes and the surrounding mesenchyme. Furthermore, both our in vivo models and in vitro cell culture studies demonstrate that loss of Tak1 results in impaired activation of the downstream MAPK target p38, as well as diminished activation of the BMP/SMAD signaling pathway. Taken together, these data demonstrate that TAK1 is a critical regulator of both MAPK and BMP signaling and is necessary for proper cartilage and joint development.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 08/2010; 25(8):1784-97. DOI:10.1002/jbmr.79 · 6.83 Impact Factor
  • Source
    • "TGF-β also inhibits G1 arrest via the up-regulation of cyclin D1 in a β-cadherin dependent manner.24 LEF1 target genes cyclin D1 and cyclin D2 are up-regulated in the favourable risk subjects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Around 80% of acute myeloid leukemia (AML) patients achieve a complete remission, however many will relapse and ultimately die of their disease. The association between karyotype and prognosis has been studied extensively and identified patient cohorts as having favourable [e.g. t(8; 21), inv (16)/t(16; 16), t(15; 17)], intermediate [e.g. cytogenetically normal (NK-AML)] or adverse risk [e.g. complex karyotypes]. Previous studies have shown that gene expression profiling signatures can classify the sub-types of AML, although few reports have shown a similar feature by using methylation markers. The global methylation patterns in 19 diagnostic AML samples were investigated using the Methylated CpG Island Amplification Microarray (MCAM) method and CpG island microarrays containing 12,000 CpG sites. The first analysis, comparing favourable and intermediate cytogenetic risk groups, revealed significantly differentially methylated CpG sites (594 CpG islands) between the two subgroups. Mutations in the NPM1 gene occur at a high frequency (40%) within the NK-AML subgroup and are associated with a more favourable prognosis in these patients. A second analysis comparing the NPM1 mutant and wild-type research study subjects again identified distinct methylation profiles between these two subgroups. Network and pathway analysis revealed possible molecular mechanisms associated with the different risk and/or mutation sub-groups. This may result in a better classification of the risk groups, improved monitoring targets, or the identification of novel molecular therapies.
    03/2010; 2:43-55. DOI:10.4137/BIC.S3185
  • Source
    • "Moreover, the expression of the cyclin B1 and cyclin D1 was found to be elevated in the LIPUS group, providing further evidence that LIPUS promotes the active division of chondrocytes [32,33]. In this regard, Li and colleagues have demonstrated that transforming growth factor beat stimulates cyclin D1 expression in chondrocytes in part through the activation of β-catenin signaling [34]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The effect of low-intensity pulsed ultrasound (LIPUS) on cell growth was examined in three-dimensional-cultured chondrocytes with a collagen sponge. To elucidate the mechanisms underlying the mechanical activation of chondrocytes, intracellular signaling pathways through the Ras/mitogen-activated protein kinase (MAPK) and the integrin/phosphatidylinositol 3 kinase (PI3K)/Akt pathways as well as proteins involved in proliferation of chondrocytes were examined in LIPUS-treated chondrocytes. Articular cartilage tissue was obtained from the metatarso-phalangeal joints of freshly sacrificed pigs. Isolated chondrocytes mixed with collagen gel and culture medium composites were added to type-I collagen honeycomb sponges. Experimental cells were cultured with daily 20-minute exposures to LIPUS. The chondrocytes proliferated and a collagenous matrix was formed on the surface of the sponge. Cell counting, histological examinations, immunohistochemical analyses and western blotting analysis were performed. The rate of chondrocyte proliferation was slightly but significantly higher in the LIPUS group in comparison with the control group during the 2-week culture period. Western blot analysis showed intense staining of type-IX collagen, cyclin B1 and cyclin D1, phosphorylated focal adhesion kinase, and phosphorylated Akt in the LIPUS group in comparison with the control group. No differences were detected, however, in the MAPK, phosphorylated MAPK and type-II collagen levels. LIPUS promoted the proliferation of cultured chondrocytes and the production of type-IX collagen in a three-dimensional culture using a collagen sponge. In addition, the anabolic LIPUS signal transduction to the nucleus via the integrin/phosphatidylinositol 3-OH kinase/Akt pathway rather than the integrin/MAPK pathway was generally associated with cell proliferation.
    Arthritis research & therapy 08/2008; 10(4):R77. DOI:10.1186/ar2451 · 3.75 Impact Factor
Show more