Mtf1 Reference Search Result - Rat Genome Database

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RGD ID	Title	Citation	Abstract	PubMed	Pub Date
11538220	Reciprocal activation of hypoxia-inducible factor (HIF)-2alpha and the zinc-ZIP8-MTF1 axis amplifies catabolic signaling in osteoarthritis.	Lee M, etal., Osteoarthritis Cartilage. 2016 Jan;24(1):134-45. doi: 10.1016/j.joca.2015.07.016. Epub 2015 Aug 1.	OBJECTIVE: Hypoxia-inducible factor (HIF)-2alpha and the zinc-ZIP8-MTF1 axis in chondrocytes serve as catabolic regulators of osteoarthritic cartilage destruction by regulating the expression of catabolic factor genes. We explored possible crosstalk between thes ... (more) e signaling pathways and its biological significance in osteoarthritis (OA). METHODS: Microarray analysis, various mRNA and protein assays were conducted using primary cultured mouse articular chondrocytes and experimental OA cartilage to reveal molecular mechanisms underlying the crosstalk between HIF-2alpha and the zinc-ZIP8-MTF1 axis. Experimental OA in mice was induced by intra-articular (IA) injection of adenovirus expressing HIF-2alpha (Ad-Epas1), ZIP8 (Ad-Zip8), or MTF1 (Ad-Mtf1) in wild-type mice or mice with cartilage-specific conditional knockout of HIF-2alpha (Epas1(fl/fl);Col2a1-Cre), ZIP8 (Zip8(fl/fl);Col2a1-Cre), or MTF1 (Mtf1(fl/fl);Col2a1-Cre). RESULTS: HIF-2alpha activated the zinc-ZIP8-MTF1 axis in chondrocytes by upregulating the Zn(2+) transporter ZIP8, thereby increasing Zn(2+) influx and activating the downstream transcription factor MTF1. The zinc-ZIP8-MTF1 axis, in turn, acted as a novel transcriptional regulator of HIF-2alpha. HIF-2alpha-induced activation of the zinc-ZIP8-MTF1 axis amplified HIF-2alpha regulation of OA cartilage destruction by synergistically promoting expression of matrix-degrading enzymes. Thus, HIF-2alpha-induced activation of the zinc-ZIP8-MTF1 axis, together with zinc-ZIP8-MTF1 regulation of HIF-2alpha, acted collectively to synergistically promote expression of matrix-degrading enzymes and OA cartilage destruction. CONCLUSION: Our findings identify a reciprocal activation mechanism involving HIF-2alpha and the zinc-ZIP8-MTF1 axis during OA pathogenesis that amplifies catabolic signaling and cartilage destruction.	26241779	2016-10-01
11572914	Zinc sensing by metal-responsive transcription factor 1 (MTF1) controls metallothionein and ZnT1 expression to buffer the sensitivity of the transcriptome response to zinc.	Hardyman JE, etal., Metallomics. 2016 Mar;8(3):337-43. doi: 10.1039/c5mt00305a.	Only a small number of genes are known direct targets of the zinc-responsive transcription factor MTF1; therefore, the aim of this study was to gain a more complete understanding of the MTF-1 regulated zinc-responsive component of the transcriptome. A targeted s ... (more) iRNA was used to deplete MTF1 expression in the human intestinal cell line Caco-2. We predicted that the response to zinc of direct MTF1 target genes would be abrogated by MTF1 knockdown. Surprisingly, a greater number of genes were regulated by zinc following MFT1 knockdown, and most genes that responded to zinc under both control and MTF1-depleted conditions had an augmented response in the latter condition. Exceptions were the zinc effluxer ZnT1 and a suite of metallothionein genes, suggesting that responses of other genes to zinc are usually buffered by increases in these proteins. We propose that MTF1 heads a hierarchy of zinc sensors, and through controlling the expression of a raft of metallothioneins and other key proteins involved in controlling intracellular zinc levels (e.g. ZnT1) alters zinc buffering capacity and total cellular zinc content. We tested and validated this model by overexpressing metallothionein and observing the predicted curtailment in response of the zinc-repressed SLC30A5 (ZnT5) promoter. The model provides the framework for an integrated understanding of cellular zinc homeostasis. Because MTs can bind metals other than zinc, this framework links with overall cellular metal homeostasis.	26824222	2016-03-01