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)

Protein transduction domains (PTDs), such as the TAT PTD, have been shown to deliver a wide variety of cargo in cell culture and to treat preclinical models of cancer and cerebral ischemia. The TAT PTD enters cells by a lipid raft-dependent macropinocytosis mechanism that all cells perform. Consequently, PTDs resemble small-molecule therapeutics in their lack of pharmacologic tissue specificity in vivo. However, several human malignancies overexpress specific receptors, including HER2 in breast cancer, GnRH in ovarian carcinomas, and CXC chemokine receptor 4 (CXCR4) in multiple malignancies. To target tumor cells that overexpress the CXCR4 receptor, we linked the CXCR4 DV3 ligand to two transducible anticancer peptides: a p53-activating peptide (DV3-TATp53C') and a cyclin-dependent kinase 2 antagonist peptide (DV3-TAT-RxL). Treatment of tumor cells expressing the CXCR4 receptor with either the DV3-TATp53C' or DV3-TAT-RxL targeted peptides resulted in an enhancement of tumor cell killing compared with treatment with nontargeted parental peptides. In contrast, there was no difference between DV3 targeted peptide and nontargeted, parental peptide treatment of non-CXCR4-expressing tumor cells. These observations show that a multidomain approach can be used to further refine and enhance the tumor selectivity of biologically active, transducible macromolecules for treating cancer.
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PMID:Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anticancer peptides. 1632 5

Interleukin-8 (IL-8), a CXC chemokine that recruits and activates inflammatory cells, plays a critical role in the pathogenesis of Behcet's disease (BD). To investigate the association of the genetic polymorphism of IL-8 and BD, we genotyped IL-8 -845 T/C, -738 T/A, -353 A/T, -251 A/T, +293 G/T, +678 T/C and receptors CXCR-1 +2607 G/C and CXCR-2 +785 C/T polymorphisms in 119 Korean patients with BD and 119 age- and sex-matched healthy blood donors. Then, single nucleotide polymorphisms (SNPs) and haplotypes were analyzed between patients and controls. There were no SNPs associated with BD. However, the frequency of haplotype TAT inferred from SNPs, IL-8 -353 A/T, -251 A/T and +678 T/C, was significantly higher in patients with BD than controls (5.9 vs 0.0%, P = 0.0001), as was haplotype ATC (6.7 vs 0.0%, P < 0.0001). The haplotype difference was still valid in human leukocyte antigen-B51-negative subjects. In conclusion, we found a significant difference in the distribution of IL-8 gene haplotypes between patients with BD and healthy controls. These results suggest that the genetic polymorphisms of proinflammatory chemokine IL-8 can contribute to the pathogenesis of BD.
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PMID:Haplotype association of IL-8 gene with Behcet's disease. 1725 14

Breast cancer is the most common cancer and the leading cause of cancer-related death among women worldwide, with urgent need to develop new therapeutics. Targeted therapy is a promising strategy for breast cancer therapy. Stromal-derived factor-1/CXC chemokine receptor 4 (CXCR4) has been implicated in the metastasis of breast cancer, which renders it to be therapeutic target. This study aimed to evaluate the anticancer effect of fused TAT- DV1-BH3 polypeptide, an antagonist of CXCR4, and investigate the underlying mechanism for the cancer cell-killing effect in the treatment of breast cancer in vitro and in vivo. This results in a potent inhibitory effect of fused TAT-DV1-BH3 polypeptide on tumor growth and metastasis in nude mice bearing established MDA-MB-231 tumors. Fused TAT-DV1-BH3 polypeptide inhibited the proliferation of MDA-MB-231 and MCF-7 cells but did not affect that of HEK-293 cells. The fused TAT-DV1-BH3 polypeptide colocalized with mitochondria and exhibited a proapoptotic effect through the regulation of caspase-9 and -3. Furthermore, the fused TAT-DV1-BH3 polypeptide suppressed the migration and invasion of the highly metastatic breast cancer cell line MDA-MB-231 in a concentration-dependent manner. Notably, the DV1-mediated inhibition of the stromal-derived factor-1/CXCR4 pathway contributed to the antimetastasis effect, evident from the reduction in the level of phosphoinositide 3 kinase and matrix metalloproteinase 9 in MDA-MB-231 cells. Collectively, these results indicate that the apoptosis-inducing effect and migration- and invasion-suppressing effect explain the tumor regression and metastasis inhibition in vivo, with the involvement of caspase- and CXCR4-mediated signaling pathway. The data suggest that the fused TAT-DV1-BH3 polypeptide is a promising agent for the treatment of breast cancer, and more studies are warranted to fully elucidate the therapeutic targets and molecular mechanism.
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PMID:Bifunctional fused polypeptide inhibits the growth and metastasis of breast cancer. 2652 62