Insulin-mediated activation of activator protein-1 through the mitogen-activated protein kinase pathway stimulates collagenase-1 gene transcription in the MES 13 mesangial cell line

Abstract

The initial stages of diabetic nephropathy are characterized, in part, by expansion of the mesangial matrix and thickening of the glomerular basement membrane which are caused by increased extracellular matrix (ECM) protein synthesis and reduced degradation, a consequence of decreased matrix metalloproteinase (MMP) activity. These changes have been largely attributed to the effects of hyperglycemia such that the potential contribution of impaired insulin action to alterations in the ECM have not been studied in detail. We have shown here that insulin stimulates collagenase-1 fusion gene transcription in the MES 13 mesangial-derived cell line. Multiple collagenase-1 promoter elements are required for the full stimulatory effect of insulin but the action of insulin appears to be mediated through an activator protein-1 (AP-1) motif. Thus, mutation of this AP-1 motif abolishes insulin-stimulated collagenase fusion gene transcription and, in isolation, this AP-1 motif can mediate a stimulatory effect of insulin on the expression of a heterologous fusion gene. This suggested that the other collagenase-1 promoter elements that are required for the full stimulatory effect of insulin probably bind accessory factors that enhance the effect of insulin mediated through the AP-1 motif. In MES 13 cells, the AP-1 motif is bound by Fra-1, Fra-2, Jun B and Jun D. Stimulation of collagenase-1 fusion gene transcription by insulin requires activation of the mitogen-activated protein kinase (MEK) pathway since inhibition of MEK-1 and -2 blocks this effect. The potential significance of these observations with respect to a role for insulin in the pathophysiology of diabetic glomerulosclerosis is discussed.

Simulating Quantitative Cellular Responses Using Asynchronous Threshold Boolean Network Ensembles

“…In other words, Figure 2a depicts a putative sequence of signaling events that could occur in a single hepatocyte after insulin stimulation. This result is qualitatively concordant with in vitro observations on AP-1 formation following insulin treatment [39]. Since the output of a single BN is binary, however, it is difficult to evaluate the activation of AP-1 to different concentrations of INS or other ligands for a single cell.…”

Administration of Pioglitazone in Low-Density Lipoprotein Receptor-Deficient Mice Inhibits Lesion Progression and Matrix Metalloproteinase Expression in Advanced Atherosclerotic Plaques

“…It has been shown previously that insulin stimulated MMP expression in human HeLa 15 and mouse MES13 kidney mesangial-derived cells. 16 O'Brien et al have reported that multiple promoter elements such as activator protein-1 (AP-1) and v-ets erythroblastosis virus E26 oncogene homolog (Ets) motifs are required for the stimulatory effect of insulin on MMP-1 gene transcription. 15 Our results as shown in Figure 4 also demonstrated that insulin stimulates MMP-13 expression by vascular SMCs.…”

“…To show if inhibition of insulin level is associated with the inhibition of MMP expression, it is important to know if insulin has stimulatory effect on MMP expression. Because previous studies have shown that insulin stimulated MMP expression in Hela 15 and mesangial cells, 16 it is tempting to know if insulin also stimulates MMP expression in vascular SMCs, the major cells in the atherosclerotic plaques. Thus, we conducted an in vitro study to determine the effect of insulin on MMP-13 expression by vascular SMCs.…”

FIAT, the factor‐inhibiting ATF4‐mediated transcription, also represses the transcriptional activity of the bZIP factor FRA‐1

“…MC3T3‐E1 osteoblastic cells were transfected with reporter targets for the FRA‐1 transcriptional targets, Mmp‐9 and Mgp 18,33,34 . Expression vectors for FIAT, c‐JUN, FRA‐1, or the tethered c‐JUN∼FRA‐1 dimer 35 were co‐transfected in various combinations with the reporter constructs.…”