Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.108 (TAT)
 2,389 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We constructed a powerful artificial cytoprotective protein, FNK, from an antiapoptotic member of the BCL-2 family, Bcl-x(L). To test the efficacy of FNK in protecting cochlear hair cells (HCs) from aminoglycoside-induced cell death in vivo, we fused FNK with protein transduction domain, TAT, of the HIV/Tat protein to construct a fusion protein of TAT-FNK. We demonstrated that, after an intraperitoneal administration to guinea pigs, TAT-myc-FNK protein was diffusely distributed in the cochlea, most prominently in the HCs and supporting cells, followed by the spiral ganglion cells, 3 hr after the injection. We next demonstrated that TAT-FNK attenuated cochlear damage induced by an ototoxic combination of kanamycin sulfate (KM) and ethacrynic acid (EA) administered at 2 different dosages: 400 mg/kg KM + 50 mg/kg EA and 200 mg/kg KM + 40 mg/kg EA. TAT-FNK or vehicle was intraperitoneally injected from 3 hr before through 5 hr after inducing the ototoxic insults, 14 days after which auditory brainstem response (ABR) and HC loss were evaluated. In comparison with vehicle-administered controls, the TAT-FNK protein significantly attenuated ototoxic drug-induced ABR threshold shifts and the extent of HC death at either dosage. The TAT-FNK protein also significantly reduced the amount of cleaved poly-(ADP-ribose) polymerase-positive HCs 8 hr after the ototoxic insults compared with that in the vehicle-administered controls. These findings indicate that systemically administered TAT-FNK was successfully delivered to the guinea pig cochlea and effectively prevented apoptotic cell death of the cochlear HCs induced by KM and EA.
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PMID:A protein derived from the fusion of TAT peptide and FNK, a Bcl-x(L) derivative, prevents cochlear hair cell death from aminoglycoside ototoxicity in vivo. 1738 7

We previously demonstrated that an artificial protein, TAT-FNK, has antiapoptotic effects against cochlear hair cell (HC) damage caused by ototoxic agents when applied systemically. To examine the feasibility of topical protein therapy for inner ear disorders, we investigated whether gelatin sponge soaked with TAT-FNK and placed on the guinea pig round window membrane (RWM) could deliver the protein to the cochlea and attenuate aminoglycoside (AG)-induced cochlear damage in vivo. First, we found that the immunoreactivity of TAT-myc-FNK was distributed throughout the cochlea. The immunoreactivity was observed from 1-24 h after application. When Tat-FNK was applied 1 h before ototoxic insult (a combination of kanamycin sulfate and ethacrynic acid), auditory brainstem response threshold shifts and the extent of HC death were significantly attenuated. When cochlear organotypic cultures prepared from P5 rats were treated with kanamycin, TAT-FNK significantly reduced the extent of caspase-9 activation and HC death. These findings indicate that TAT-FNK topically applied on the RWM can enter the cochlea by diffusion and effectively prevent AG-induced apoptosis of cochlear HCs by suppressing the mitochondrial caspase-9 pathway.
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PMID:Topical application of the antiapoptotic TAT-FNK protein prevents aminoglycoside-induced ototoxicity. 2218 15