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)

The delivery of proteins across the blood-brain barrier is severely limited by their size and biochemical properties. Numerous peptides have been characterized in recent years that prevent neuronal death in vitro, but cannot be used therapeutically, since they do not cross cell membrane barriers. It has been shown in the 1990s that the HIV TAT protein is able to cross cell membranes even when coupled with larger peptides. It appears, therefore, that TAT fusion proteins may enter the brain, even when used systemically. Indeed, the systemic delivery of a TAT protein linked with glial-derived neurotrophic factor (GDNF) successfully transduced central nervous system (CNS) neurons in mice. When administered after optic nerve transection and focal cerebral ischemia, TAT-GDNF protected retinal ganglion cells and brain neurons from cell death, elevated tissue Bcl-XL levels and attenuated the activity of the executioner caspase-3. These findings demonstrate the in vivo efficacy of fusion proteins in clinically relevant disease models, raising hopes that neuroprotection may become eventually feasible in human patients.
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PMID:TAT-GDNF in neurodegeneration and ischemic stroke. 1661 36

Glial-cell-line-derived neurotrophic factor (GDNF) acts as a potent survival factor for many neuronal populations, including retinal ganglion cells (RGC), indicating a potential therapeutic role of GDNF for neurological disorders. To enhance the tissue distribution and applicability of the neurotrophin, we linked it to a protein transduction domain derived from the HIV TAT protein and tested it in a well-established model for traumatic injury in the CNS: After optic nerve axotomy, the number of surviving RGCs was significantly increased in mice injected with TAT-GDNF on days 0, 3, 7, and 10 after surgery compared with GDNF- or PBS-injected animals. Moreover, TAT-GDNF reduced the number of activated caspase-3-positive cells. These results show that the neuroprotective effect of substances like neurotrophins may be enhanced by linking them to a domain that has been shown to mediate efficient transduction across biological membranes.
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PMID:The TAT protein transduction domain enhances the neuroprotective effect of glial-cell-line-derived neurotrophic factor after optic nerve transection. 1690 73

Neurotrophic factors play an important role in the development and maintenance of not only neural but also nonneural tissues. Several neurotrophic factors are expressed in dental tissues, but their role in tooth development is not clear. Here, we report that neurotrophic factor neurotrophin (NT)-4 promotes differentiation of dental epithelial cells and enhances the expression of enamel matrix genes. Dental epithelial cells from 3-day-old mice expressed NT-4 and three variants of TrkB receptors for neurotrophins (full-length TrkB-FL and truncated TrkB-T1 and -T2). Dental epithelial cell line HAT-7 expressed these genes, similar to those in dental epithelial cells. We found that NT-4 reduced HAT-7 cell proliferation and induced the expression of enamel matrix genes, such as ameloblastin (Ambn). Transfection of HAT-7 cells with the TrkB-FL expression construct enhanced the NT-4-mediated induction of Ambn expression. This enhancement was blocked by K252a, an inhibitor for Trk tyrosine kinases. Phosphorylation of ERK1/2, a downstream molecule of TrkB, was induced in HAT-7 cells upon NT-4 treatment. TrkB-FL but not TrkB-T1 transfection increased the phosphorylation level of ERK1/2 in NT-4-treated HAT-7 cells. These results suggest that NT-4 induced Ambn expression via the TrkB-MAPK pathway. The p75 inhibitor TAT-pep5 decreased NT-4-mediated induction of the expression of Ambn, TrkB-FL, and TrkB-T1, suggesting that both high affinity and low affinity neurotrophin receptors were required for NT-4 activity. We found that NT-4-null mice developed a thin enamel layer and had a decrease in Ambn expression. Our results suggest that NT-4 regulates proliferation and differentiation of the dental epithelium and promotes production of the enamel matrix.
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PMID:Neurotrophic factor neurotrophin-4 regulates ameloblastin expression via full-length TrkB. 1804 80