Disease relevance of Fbxo32

• Atrogin1/MAFbx is an ubiquitin ligase that mediates muscle atrophy in a variety of catabolic states [1].
• Conversely, downregulation of atrogin-1 using adenoviral small interfering RNA (siRNA) expression enhances agonist-induced calcineurin activity and cardiomyocyte hypertrophy [2].
• Consistent with these cellular observations, overexpression of atrogin-1 in hearts of transgenic mice reduces calcineurin protein levels and blunts cardiac hypertrophy after banding of the thoracic aorta [2].
• Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1 [3].
• This procedure results in the production of elevated levels of circulating mTNFalpha followed by body weight loss, upregulation of Atrogin1, and muscle atrophy, including muscles distant from the site of gene transfer [4].
• Transgenic mice expressing atrogin-1 in the heart displayed increased Foxo1 ubiquitylation and upregulation of known Forkhead target genes concomitant with suppression of cardiac hypertrophy, while mice lacking atrogin-1 displayed the opposite physiologic phenotype [5].

High impact information on Fbxo32

• Moreover, constitutively active Foxo3 acts on the atrogin-1 promoter to cause atrogin-1 transcription and dramatic atrophy of myotubes and muscle fibers [6].
• When Foxo activation is blocked by a dominant-negative construct in myotubes or by RNAi in mouse muscles in vivo, atrogin-1 induction during starvation and atrophy of myotubes induced by glucocorticoids are prevented [6].
• Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy [6].
• We demonstrate that a muscle-specific F-box protein called atrogin-1, or muscle atrophy F-box, directly interacts with calcineurin A and alpha-actinin-2 at the Z-disc of cardiomyocytes [2].
• Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex [2].

Chemical compound and disease context of Fbxo32

• Muscle atrophy after 4 d of high-dose dexamethasone was associated with increased mRNA of enzymes involved in proteolytic pathways (atrogin-1, muscle ring finger 1, and cathepsin L) and increased chymotrypsin-like proteasomal activity [7].

Biological context of Fbxo32

• We recently found that H2O2 stimulates atrogin1/MAFbx gene expression [1].
• Transfection of PGC-1alpha into adult fibers reduced the capacity of FoxO3 to cause fiber atrophy and to bind to and transcribe from the atrogin-1 promoter [8].
• MAFbx levels were greatly enhanced upon myogenic differentiation of C2C12 myoblasts, and differentiation markedly increased activity of a reporter gene constructed with 400 bp of upstream promotor from the MAFbx gene [9].

Anatomical context of Fbxo32

• FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart [10].
• In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression [10].

Associations of Fbxo32 with chemical compounds

• MAFbx associates with MyoD through an inverted LXXLL motif located in a series of helical leucine-charged residue-rich domains [11].
• Similarly, whereas dexamethasone increased atrogene expression, pretreatment with the glucocorticoid receptor antagonist RU-486 failed to ameliorate the sepsis-induced increase in atrogin-1 and MuRF1 [12].
• We investigated the differential expression of atrogin-1 and FBXO25 in fasted and dexamethasone-treated mice and also in rats with streptozotocin-induced diabetes [13].
• We also demonstrate that mRNA levels of the ubiquitin ligases atrogin-1 and muscle ring finger-1 are upregulated in angiotensin II-infused WT, but not in IGF-1-transgenic, mice [14].

Physical interactions of Fbxo32

• A core LXXLL motif sequence in MyoD is necessary for binding to MAFbx [11].

Regulatory relationships of Fbxo32

• As with H2O2, we found that TNF-alpha exposure up-regulates atrogin1/MAFbx mRNA within 2 h in C2C12 myotubes [1].
• Overexpression of MAFbx suppresses MyoD-induced differentiation and inhibits myotube formation [11].

Other interactions of Fbxo32

• Intraperitoneal injection of TNF-alpha increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h [1].
• In atrophying muscles, the ubiquitin ligase, atrogin-1 (MAFbx), is dramatically induced, and this response is necessary for rapid atrophy [6].
• Dexamethasone induced a twofold increase of atrogin-1 mRNA; again, only L6 myotubes were susceptible [15].

Analytical, diagnostic and therapeutic context of Fbxo32

• 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 [8].
• 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 [12].
• Using a RT-PCR, we demonstrated that FBXO25 is highly expressed in brain, kidney, and intestine, whereas atrogin-1 expression is largely restricted to striate muscle [13].

References