Disease relevance of TRIM63

• Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases [1].
• MURF-1, the only family member expressed throughout development, has been implicated in several studies as an ubiquitin ligase that is upregulated in response to multiple stimuli during muscle atrophy [2].
• In cardiac hypertrophy, Atrogin1 and MuRF1 attenuate cardiac hypertrophy by interacting with calcineurin and PKCepsilon, respectively [3].
• Additionally, peritonitis produced by cecal ligation and puncture increased atrogin-1 and MuRF1 mRNA in gastrocnemius (but not soleus or heart) by 8 h, which was sustained for 72 and 24 h, respectively [4].
• The KSHV open reading frame K9 encodes the viral interferon (IFN) factor 1 (vIRF1), which downregulates IFN- and IRF-mediated transcriptional activation, and leads to cellular transformation in rodent fibroblasts and induction of tumors in nude mice [5].

Psychiatry related information on TRIM63

• The IRF also showed the fewest significant differences between the means of the estimated MMPI scale scores and those that actually were obtained [6].

High impact information on TRIM63

• Expression of the E3 ligase MuRF1, a mediator of muscle atrophy, was increased in MIKK mice [7].
• Maxicircle-encoded guide RNAs (gRNAs) for cytochrome b and maxicircle unidentified reading frames 2 and 3 (MURF2 and MURF3) were isolated by hybrid selection and sequenced [8].
• Uridine additions and deletions in the 5' ends of the COIII, MURF2, and MURF3 transcripts create new N-terminal amino acid sequences that are conserved between species, and new AUG initiation codons in several cases [9].
• Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy [10].
• This perspective will focus on the signalling pathways that control skeletal muscle atrophy and hypertrophy, including the recently identified ubiquitin ligases muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), as a basis to develop targets for pharmacologic intervention in muscle disease [11].

Biological context of TRIM63

• The dual interactions of MURF-1 with titin and GMEB-1 may link myofibril signaling pathways (perhaps including titin's kinase domain) with muscle gene expression [12].
• Transient transfection of SMRZ into C2C12 myoblasts showed localization of SMRZ to the nucleus [13].
• Fluorescence in situ hybridization localized SMRZ to chromosome 1p33-34 [13].
• These data suggest that SMRZ may play an important role in striated muscle cell embryonic development and perhaps in cell cycle regulation [13].
• Searches of a human heart expressed sequence tag data base for genes encoding the RING domain identified a novel cDNA, named striated muscle RING zinc finger protein (SMRZ) [13].

Anatomical context of TRIM63

• To investigate the functional significance of this interaction, we expressed green fluorescent protein fusion constructs encoding defined fragments of titin's M-line region and MURF-1 in cardiac myocytes [12].
• Consistent with our in vitro binding data implicating MURF-1 with nuclear functions, endogenous MURF-1 also was detected in the nuclei of some myocytes [12].
• Functional properties of the titin/connectin-associated proteins, the muscle-specific RING finger proteins (MURFs), in striated muscle [2].
• MURF-2 is developmentally down-regulated and is assembled at the M-line region of the sarcomere and with microtubules [2].
• MuRF1 reduced steady-state troponin I levels when coexpressed in COS-7 cells and increased degradation of endogenous troponin I protein in cardiomyocytes [14].

Associations of TRIM63 with chemical compounds

• Changes in overall proteolysis with Dex and IGF-I correlated tightly with changes in atrogin-1 mRNA content, but not with changes in MuRF1 mRNA [15].
• Finally, administration of the glucocorticoid receptor antagonist RU-486 did not prevent burn-induced atrophy of the gastrocnemius or the associated elevation in atrogin-1, MuRF-1, or polyUb [16].
• Insulin and insulin-like growth factor-1 act through the phosphoinositide 3-kinase/AKT pathway to suppress the expression of two of these enzymes, MuRF1 and MAFbx/atrogin-1 [17].
• Thus, under in vivo conditions in mature adult rats, the sepsis-induced increase in muscle atrogin-1 and MuRF1 mRNA appears both glucocorticoid and TNF independent and is unresponsive to leucine [4].
• The aim of this study was to examine the effect of polyethylene glycol linked to soluble TNFRI (PEG-sTNFRI) on gene expression of the atrogens MuRF-1 and MAFbx in skeletal muscle of arthritic rats [18].

Regulatory relationships of TRIM63

• Four hours after administration of the anabolic agent insulin-like growth factor (IGF)-I to burned rats, the mRNA content of atrogin-1 and polyUb in gastrocnemius had returned to control values and the elevation in MuRF-1 was reduced 50% [16].

Other interactions of TRIM63

• Cell culture studies suggest that MURF-1 specifically has a role in maintaining titin M-line integrity and yeast two-hybrid studies point toward its participation in muscle stress response pathways and gene expression [2].
• Therefore, IGF-1/Akt and TNFalpha represent potential mediators implicated in the regulation of MuRF1 and atrogin-1 genes during aging [19].
• This response occurred despite fully blunting the increases in the mRNA for of atrogin-1, MURF-1, and myostatin, e.g., sensitive gene markers of an activated catabolic state [20].
• The gene expression and activity of calpains and the muscle wasting-associated ubiquitin ligases, atrogin-1 and MuRF1, are not altered in patients with primary hyperparathyroidism [21].
• Genes, found in this region, include 12S and 9S ribosomal RNAs, subunits 7, 8 and 9 of NADH dehydrogenase (ND7, ND8 and ND9) and subunit 6 of ATPase (A6 or MURF4), as well as the genes (MURF1, MURF5 and G3) with unknown function [22].

Analytical, diagnostic and therapeutic context of TRIM63

• Northern blots demonstrated that SMRZ is expressed exclusively in striated muscle [13].
• Furthermore, in transgenic mice overexpressing PGC-1alpha, denervation and fasting caused a much smaller decrease in muscle fiber diameter and a smaller induction of atrogin-1 and MuRF-1 than in control mice [23].
• After 48 h of burn injury (40% total body surface area full-thickness scald burn) gastrocnemius weight was reduced, and this change was associated with an increased mRNA abundance for atrogin-1 and MuRF-1 (3.1- to 8-fold, respectively) [16].
• A biopsy was obtained from the sternohyoid muscle in patients undergoing surgery for primary HPT (n=8) and in normocalcemic control patients undergoing thyroid surgery (n=11). mRNA levels for atrogin-1, MuRF1 and the calcium-regulated proteases, mu- and m-calpain, were determined by real-time PCR [21].
• The expression of MAFbx/Murf-1 and troponin I was analyzed by RT-PCR and Western blotting in the non-infarcted area of the left ventricle [24].

References