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)

Schwannoma tumors, which occur sporadically and in patients with neurofibromatosis, account for 8% of intracranial tumors and can only be treated by surgical removal. Most schwannomas have biallelic mutations in the NF2 tumor suppressor gene. We previously showed that schwannoma-derived Schwann cells exhibit membrane ruffling and aberrant cell spreading when plated onto laminin, indicative of fundamental F-actin cytoskeletal defects. Here we expand these observations to a large group of sporadic and NF2-related tumors and extend them to schwannomatosis-derived tumors. Mutation at NF2 correlated with F-actin abnormalities, but the extent of morphological change did not correlate with the type of NF2 mutation. We used a recently described molecular strategy, TAT-mediated protein transfer, to acutely introduce the NF2 protein, merlin, into primary human schwannoma cells in an attempt to reverse the cytoskeletal phenotype. Abnormal ruffling and cell spreading by cells with identified NF2 mutations were rapidly reversed by introduction of TAT-merlin. The effect is specific to TAT-merlin isoform 1, the growth-suppressive isoform of merlin. TAT-merlin isoform 2, a TAT-merlin mutant (L64P), and merlin lacking TAT were ineffective in reversing the cytoskeletal phenotype. Results show that merlin isoform 1 is sufficient to restore normal actin organization in NF2-deficient human tumor cells, demonstrating a key role for merlin in the NF2 phenotype. These results lay the foundation for epigenetic complementation studies in NF2 mouse models and possibly for experiments to evaluate the utility of merlin transduction into patients as protein therapy.
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PMID:The neurofibromatosis type 2 gene product, merlin, reverses the F-actin cytoskeletal defects in primary human Schwannoma cells. 1180 6

So far no effective therapeutic has been developed for the FDA-approved treatment of ovarian cancer patients. Recently we provided the first evidence indicating that an old antibiotic (antiparasitic drug) called Ivermectin suppresses the growth of a variety of human ovarian cancer cell lines in vitro by inactivating the oncogenic kinase PAK1 somehow (Hashimoto H, et al. Drug Discov Ther. 2009;3:243-246). This kinase is now known to be essential for the growth of more than 70% of all human cancers including breast, prostate, pancreatic, colon, gastric, lung, cervical, thyroid cancers as well as hepatoma, glioma, melanoma, MM (multiple myeloma) and NF (neurofibromatosis) tumors. In this study, using the cell-permeable PAK1-inactivating peptide TAT-PAK18 which blocks the essential PAK1-PIX interaction, we examined the relationship between the sensitivity of ovarian cancer cell lines to this anti-PAK1 peptide and the protein expression/autophosphorylation levels of PAK1 in these cell lines, and found that the more PAK1 is abnormally activated (autophosporylated at Thr 423), the more their growth is sensitive to this peptide, regardless of their PAK1 expression levels. This observation provides the first direct evidence that ovarian cancers also belong to the PAK1-dependent cancers which represent more than 70% of all human cancers, suggesting that anti-PAK1 drugs would be effective therapeutics for ovarian cancers.
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PMID:The direct PAK1 inhibitor, TAT-PAK18, blocks preferentially the growth of human ovarian cancer cell lines in which PAK1 is abnormally activated by autophosphorylation at Thr 423. 2249 Nov 45