Fine-tuned regulation of the PGC-1α gene transcription by different intracellular signaling pathways

It has previously been known that transcription of the PGC-1α gene can be either inhibited or stimulated by p38 MAP kinase (p38 MAPK). To determine whether p38 MAPK plays an inhibitory or stimulatory role in PGC-1α gene transcription, we further investigated the role of p38 MAPK in this study. Our results showed that the basal level of p38 MAPK phosphorylation was increased in gastrocnemius of mice under HFD and that p38 MAPK stimulated PGC-1α gene transcription in C2C12 myotubes. Our results also provided new mechanisms in myotubes that the p38 MAPK-induced PGC-1α gene transcription was mediated by CREB. In exploring the role of the Akt-dependent insulin signaling on PGC-1α gene transcription, we found that the basal Akt-dependent signaling was increased in gastrocnemius of mice under HFD. The p38 MAPK-induced PGC-1α gene transcription was prevented by insulin. Insulin suppression of PGC-1α gene transcription was neutralized by overexpression of the constitutively nuclear form of FoxO1. Finally, we located three insulin response elements (IREs) in the PGC-1α promoter, and mutations of these IREs abolish or blunt activity of the PGC-1α promoter. Together, our results show that transcription of the PGC-1α gene is balanced by different intracellular signaling pathways.

Download Full-text

Stimulation of pro-α1(I) collagen by TGF-β1 in mesangial cells: role of the p38 MAPK pathway

AJP Renal Physiology ◽

10.1152/ajprenal.2001.280.3.f495 ◽

2001 ◽

Vol 280 (3) ◽

pp. F495-F504 ◽

Cited By ~ 92

Author(s):

Beek Yoke Chin ◽

Amir Mohsenin ◽

Su Xia Li ◽

Augustine M. K. Choi ◽

Mary E. Choi

Keyword(s):

P38 Mapk ◽

Intracellular Signaling ◽

Mesangial Cells ◽

Mapk Pathway ◽

Dominant Negative ◽

Glomerular Mesangial Cells ◽

Mapk Activation ◽

Mapk Phosphorylation ◽

Collagen Mrna

Transforming growth factor-β1(TGF-β1) is a potent inducer of extracellular matrix protein synthesis and a key mediator of renal fibrosis. However, the intracellular signaling mechanisms by which TGF-β1stimulates this process remain incompletely understood. In this report, we examined the role of a major stress-activated intracellular signaling cascade, belonging to the mitogen-activated protein kinase (MAPK) superfamily, in mediating TGF-β1 responses in rat glomerular mesangial cells, using dominant-negative inhibition of TGF-β1 signaling receptors. We first stably transfected rat glomerular mesangial cells with a kinase-deleted mutant TGF-β type II receptor (TβR-IIM) designed to inhibit TGF-β1 signaling in a dominant-negative fashion. Next, expression of TβR-IIM mRNA was confirmed by Northern analysis. Cell surface expression and ligand binding of TβR-IIM protein were demonstrated by affinity cross-linking with 125I-labeled-TGF-β1. TGF-β1 rapidly induced p38 MAPK phosphorylation in wild-type and empty vector (pcDNA3)-transfected control mesangial cells. Interestingly, transfection with dominant-negative TβR-IIM failed to block TGF-β1-induced p38 MAPK phosphorylation. Moreover, dominant-negative TβR-IIMfailed to block TGF-β1-stimulated pro-α1(I) collagen mRNA expression and cellular protein synthesis, whereas TGF-β1-induced extracellular signal-regulated kinase (ERK) 1/ERK2 activation and antiproliferative responses were blocked by TβR-IIM. In the presence of a specific inhibitor of p38 MAPK, SB-203580, TGF-β1 was unable to stimulate pro-α1(I) collagen mRNA expression in the control and TβR-IIM-transfected mesangial cells. Finally, we confirmed that both p38 MAPK activation and pro-α1(I) collagen stimulation were TGF-β1 effects that were abrogated by dominant-negative inhibition of TGF-β type I receptor. Thus we show first demonstration of p38 MAPK activation by TGF-β1 in mesangial cells, and, given the rapid kinetics, this TGF-β1 effect is likely a direct one. Furthermore, our findings suggest that the p38 MAPK pathway functions as a component in the signaling of pro-α1(I) collagen induction by TGF-β1 in mesangial cells.

Download Full-text

Pathological processes and therapeutic advances in radioiodide refractory thyroid cancer

Journal of Molecular Endocrinology ◽

10.1530/jme-17-0134 ◽

2017 ◽

Vol 59 (4) ◽

pp. R141-R154 ◽

Cited By ~ 4

Author(s):

Marika H Tesselaar ◽

Johannes W Smit ◽

James Nagarajah ◽

Romana T Netea-Maier ◽

Theo S Plantinga

Keyword(s):

Thyroid Cancer ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Medullary Thyroid Cancer ◽

Disease Remission ◽

Intracellular Signaling Pathways ◽

Oncogenic Mutations ◽

Diagnostics And Therapy ◽

Disease Present

While in most patients with non-medullary thyroid cancer (TC), disease remission is achieved by thyroidectomy and ablation of tumor remnants by radioactive iodide (RAI), a substantial subgroup of patients with metastatic disease present tumor lesions that have acquired RAI resistance as a result of dedifferentiation. Although oncogenic mutations inBRAF,TERTpromoter andTP53are associated with an increased propensity for induction of dedifferentiation, the role of genetic and epigenetic aberrations and their effects on important intracellular signaling pathways is not yet fully elucidated. Also immune, metabolic, stemness and microRNA pathways have emerged as important determinants of TC dedifferentiation and RAI resistance. These signaling pathways have major clinical implications since their targeting could inhibit TC progression and could enable redifferentiation to restore RAI sensitivity. In this review, we discuss the current insights into the pathological processes conferring dedifferentiation and RAI resistance in TC and elaborate on novel advances in diagnostics and therapy to improve the clinical outcome of RAI-refractory TC patients.

Download Full-text