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10.1152/ajprenal.00406.2014 http://scihub22266oqcxt.onion/10.1152/ajprenal.00406.2014 C4254973!4254973 !25234309     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=25234309 &cmd=llinks): Failed to open stream: HTTP request failed! 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Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels |pdf=|usr=}}{{25234309 }} gab.com Text Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels JO: Am J Physiol Renal Physiol http://www.kidney.de/pget.php?&tw=1&pmid=25234309 #FOAvip Autosomal-dominant polycystic kidney disease (ADPKD) is a progressive, proliferative renal disease. Kidneys from ADPKD patients are characterized by the presence of cysts that are marked by enhanced proliferation and apoptosis of renal tubular epithelial cells. Current treatment of this disease is supportive, as there are few if any clinically validated targeted therapeutics. Given the parallels between cystic disease and cancer, and in light of our findings of the efficacy of the nuclear transport inhibitors in kidney cancer, which has similarities to ADPKD, we asked whether such inhibitors show utility in ADPKD. In this study, we tested selective inhibitors of nuclear export (SINE) in two human ADPKD cell lines and in an in vivo mouse model of ADPKD. After effective downregulation of a nuclear exporter, exportin 1 (XPO1), with KPT-330, both cell lines showed dose-dependent inhibition of cell proliferation through G?/G? arrest associated with downregulation of CDK4, with minimal apoptosis. To analyze mechanisms of CDK4 decrease by XPO1 inhibition, localization of various XPO1 target proteins was examined, and C/EBP? was found to be localized in the nucleus by XPO1 inhibition, resulting in an increase of C/EBP?, which activates degradation of CDK4. Furthermore, inhibition of XPO1 with the parallel inhibitor KPT-335 attenuated cyst growth in vivo in the PKD1 mutant mouse model Pkd1(v/v). Thus, inhibition of nuclear export by KPT-330, which has shown no adverse effects in renal serum chemistries and urinalyses in animal models, and which is already in phase 1 trials for cancers, will be rapidly translatable to human ADPKD. Twit Text FOAVip Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels ????Am J Physiol Renal Physiol http://www.kidney.de/pget.php?&tw=1&pmid=25234309 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=25234309 #FOAvip English Wikipedia <ref>{{Cite pmid|25234309 }}</ref> Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels #MMPMID25234309 Tan M ; Wettersten HI ; Chu K ; Huso DL ; Watnick T ; Friedlander S ; Landesman Y ; Weiss RH Am J Physiol Renal Physiol 2014[Dec]; 307 (11 ): F1179-86 PMID25234309 show ga Autosomal-dominant polycystic kidney disease (ADPKD) is a progressive, proliferative renal disease. Kidneys from ADPKD patients are characterized by the presence of cysts that are marked by enhanced proliferation and apoptosis of renal tubular epithelial cells. Current treatment of this disease is supportive, as there are few if any clinically validated targeted therapeutics. Given the parallels between cystic disease and cancer, and in light of our findings of the efficacy of the nuclear transport inhibitors in kidney cancer, which has similarities to ADPKD, we asked whether such inhibitors show utility in ADPKD. In this study, we tested selective inhibitors of nuclear export (SINE) in two human ADPKD cell lines and in an in vivo mouse model of ADPKD. After effective downregulation of a nuclear exporter, exportin 1 (XPO1), with KPT-330, both cell lines showed dose-dependent inhibition of cell proliferation through G?/G? arrest associated with downregulation of CDK4, with minimal apoptosis. To analyze mechanisms of CDK4 decrease by XPO1 inhibition, localization of various XPO1 target proteins was examined, and C/EBP? was found to be localized in the nucleus by XPO1 inhibition, resulting in an increase of C/EBP?, which activates degradation of CDK4. Furthermore, inhibition of XPO1 with the parallel inhibitor KPT-335 attenuated cyst growth in vivo in the PKD1 mutant mouse model Pkd1(v/v). Thus, inhibition of nuclear export by KPT-330, which has shown no adverse effects in renal serum chemistries and urinalyses in animal models, and which is already in phase 1 trials for cancers, will be rapidly translatable to human ADPKD. |Active Transport, Cell Nucleus/*drug effects [MESH] |Animals [MESH] |Cell Cycle Checkpoints/*drug effects [MESH] |Cell Line [MESH] |Cell Proliferation/drug effects [MESH] |Cyclin-Dependent Kinase 4/*biosynthesis [MESH] |Cysts/*pathology [MESH] |Exportin 1 Protein [MESH] |Humans [MESH] |Hydrazines/pharmacology [MESH] |Karyopherins/antagonists & inhibitors [MESH] |Mice [MESH] |Polycystic Kidney, Autosomal Dominant/*drug therapy/*pathology [MESH] |Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors [MESH] |TRPP Cation Channels/genetics/metabolism [MESH]Novel inhibitors of nuclear transport cause cell cycle arrest and decr(epmc).pdf DeepDyve Pubget Overpricing