ATF4 is an osteoblast-enriched transcription factor of the leucine zipper family. We recently identified that vimentin, a leucine zipper-containing intermediate filament protein, suppresses ATF4-dependent osteocalcin (Ocn) transcription and osteoblast differentiation. Here we show that TGFβ inhibits ATF4-dependent activation of Ocn by up-regulation of vimentin expression. Osteoblasts lacking At...

PURPOSE To determine whether inhibition of TGFβ signaling prior to irradiation sensitizes human and murine cancer cells in vitro and in vivo. EXPERIMENTAL DESIGN TGFβ-mediated growth and Smad phosphorylation of MCF7, Hs578T, MDA-MB-231, and T47D human breast cancer cell lines were examined and correlated with clonogenic survival following graded radiation doses with and without pretreatment w...

Lysophosphatidic acid (LPA) is a multifunctional intercellular phospholipid mediator present in blood and other biological fluids. In cancer cells, LPA stimulates expression or activity of inflammatory cytokines, angiogenic factors, matrix metalloproteinases, and other oncogenic proteins. In this study, we showed that LPA upregulated expression of the cyclin-dependent kinase inhibitor p21(Waf1)...

(TGFβ) is a major contributing factor to many diseases including progressive cancers [1]. Given the normal homeostatic functions of TGFβ in controlling cell proliferation, immune surveillance and angiogenesis, however, it is much less clear which cancer patients would derive clinical benefit from the administration of anti-TGFβ targeted therapy. The use of these therapies is complicated not onl...

Glycoprotein-A repetitions predominant protein (GARP) associates with latent transforming growth factor-β (proTGFβ) on the surface of T regulatory cells and platelets; however, whether GARP functions in latent TGFβ activation and the structural basis of coassociation remain unknown. We find that Cys-192 and Cys-331 of GARP disulfide link to the TGFβ1 prodomain and that GARP with C192A and C331A...

In many renal diseases, transforming growth factor β (TGFβ)-stimulated canonical Smad 3 and noncanonical mechanistic target of rapamycin (mTOR) promote increased protein synthesis and mesangial cell hypertrophy. The cellular underpinnings involving these signaling molecules to regulate mesangial cell hypertrophy are not fully understood. Deptor has recently been identified as an mTOR interactin...

Epithelial-mesenchymal-transition (EMT) is a fundamental cellular process that is critical for normal development and tumor metastasis. The transforming growth factor beta (TGFβ) is a potent inducer of EMT like effects, but the mechanisms that regulate TGFβ-induced EMT remain incompletely understood. Using the widely employed NMuMG mammary epithelial cells as a model to study TGFβ-induced EMT, ...

Triple negative breast cancer (TNBC), an aggressive subtype of breast cancer, display poor prognosis and exhibit resistance to conventional therapies, partly due to an enrichment in breast cancer stem cells (BCSCs). Here, we investigated the role of the cyclooxygenase-2 (COX-2), a downstream target of TGFβ, in regulating BCSCs in TNBC. Bioinformatics analysis revealed that COX-2 is highly expre...

Myocardial infarction (MI) is a major form of heart disease that leads to immediate cardiomyocyte death due to ischemia and eventually fibrosis and scar formation and further dysfunction of myocardium and heart failure. Extracellular matrix (ECM) production and tissue repair is conducted by myofibroblasts, which are formed from the normal quiescent cardiac fibroblasts following transformational...

UNLABELLED In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identified cAMP-responsive element-binding protein 1 ...