The subunit assembly state of the Mediator complex is nutrient-regulated and is dysregulated in a genetic model of insulin resistance and obesity.

08:00 EDT 26th April 2019 | BioPortfolio

Summary of "The subunit assembly state of the Mediator complex is nutrient-regulated and is dysregulated in a genetic model of insulin resistance and obesity."

The Mediator complex plays a critical role in the regulation of transcription by linking transcription factors to RNA polymerase II. By examining mouse livers, we have found that in the fasted state, the Mediator complex exists primarily as an approximate 1.2 MDa complex, consistent with the size of the large Mediator complex, whereas following feeding it converts to an approximate 600 kDa complex, consistent with the size of the core Mediator complex. This dynamic change is due to the dissociation and degradation of the kinase module that includes the MED13, MED12, cyclin-dependent kinase 8 (CDK8) and Cyclin C (CCNC) subunits. The dissociation and degradation of the kinase module are dependent upon nutrient activation of mTORC1 that is necessary for the induction of lipogenic gene expression because pharmacological or genetic inhibition of mTORC1 in the fed state restores the kinase module. The degradation but not dissociation of the kinase module is dependent upon the E3 ligase, SCFFBW7. In addition, genetically insulin resistant and obese db/db mice in the fasted state displayed elevated lipogenic gene expression and loss of the kinase module that was reversed following mTORC1 inhibition. These data demonstrate that the assembly state of the Mediator complex undergoes physiologic regulation during normal cycles of fasting and feeding in mouse liver. Furthermore, the assembly state of the Mediator complex is dysregulated in states of obesity and insulin resistance.


Journal Details

This article was published in the following journal.

Name: The Journal of biological chemistry
ISSN: 1083-351X


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Medical and Biotech [MESH] Definitions

A mediator complex subunit that is believed to play a key role in the coactivation of nuclear receptor-activated transcription by the mediator complex. It interacts with a variety of nuclear receptors including RETINOIC ACID RECEPTORS; THYROID HORMONE RECEPTORS; VITAMIN D RECEPTORS; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS; ESTROGEN RECEPTORS; and GLUCOCORTICOID RECEPTORS.

C5 plays a central role in both the classical and the alternative pathway of COMPLEMENT ACTIVATION. C5 is cleaved by C5 CONVERTASE into COMPLEMENT C5A and COMPLEMENT C5B. The smaller fragment C5a is an ANAPHYLATOXIN and mediator of inflammatory process. The major fragment C5b binds to the membrane initiating the spontaneous assembly of the late complement components, C5-C9, into the MEMBRANE ATTACK COMPLEX.

A large protein complex which acts as a signaling adaptor protein that allows communication between the various regulatory and functional components of GENETIC TRANSCRIPTION including DNA POLYMERASE II; GENERAL TRANSCRIPTION FACTORS; and TRANSCRIPTION FACTORS that are bound to upstream ENHANCER ELEMENTS. The mediator complex was originally studied in YEAST where at least 21 subunits were identified. Many of the yeast subunits are homologs to proteins in higher organisms that are found associated with specific nuclear receptors such as THYROID HORMONE RECEPTORS and VITAMIN D RECEPTORS.

A heterodimeric complex of STAT1 PROTEIN and STAT2 PROTEIN that interacts with ISGF3GAMMA and is a subunit of the ISGF3 COMPLEX.

A formulation for presenting an antigen to induce specific immunologic responses. It consists of an assembly of antigens in multimeric form. The assembly is attached to a matrix with a built-in adjuvant, saponin. ISCOMs induce strong serum antibody responses, and are used as highly immunogenic forms of subunit vaccines.

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