Reference - Detail
| RRC ID | 43405 |
|---|---|
| Author | Gingery A, Bradley EW, Pederson L, Ruan M, Horwood NJ, Oursler MJ. |
| Title | TGF-beta coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival. |
| Journal | Exp Cell Res |
| Abstract |
To better understand the roles of TGF-beta in bone metabolism, we investigated osteoclast survival in response TGF-beta and found that TGF-beta inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-beta receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-beta treatment. Since osteoclast survival involves MEK, AKT, and NFkappaB activation, we examined TGF-beta effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IkappaB, and NFkappaB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFkappaB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFkappaB repressed TGF-beta-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-beta-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX(L) expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-beta-induced NFkappaB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-beta to support of osteoclast survival. |
| Volume | 314(15) |
| Pages | 2725-38 |
| Published | 2008-9-10 |
| DOI | 10.1016/j.yexcr.2008.06.006 |
| PII | S0014-4827(08)00238-3 |
| PMID | 18586026 |
| PMC | PMC2578840 |
| MeSH | Animals Bone and Bones / enzymology* Cell Line Cell Survival / drug effects Cell Survival / physiology Cells, Cultured Enzyme Activation / drug effects Enzyme Activation / physiology Gene Expression Regulation, Enzymologic / drug effects Gene Expression Regulation, Enzymologic / physiology MAP Kinase Kinase 1 / metabolism MAP Kinase Kinase Kinases / metabolism Mice Mice, Inbred BALB C NF-kappa B / metabolism Osteoclasts / drug effects Osteoclasts / enzymology* Phosphorylation Phosphotransferases / metabolism* Proto-Oncogene Proteins c-akt / metabolism Signal Transduction / drug effects Signal Transduction / physiology* Smad1 Protein / metabolism* Transcriptional Activation / drug effects Transcriptional Activation / physiology Transforming Growth Factor beta / metabolism* Transforming Growth Factor beta / pharmacology |
| IF | 3.383 |
| Times Cited | 123 |
| WOS Category | ONCOLOGY CELL BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| Total number of mentions | 0 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | ST2(RCB0224) |