Use my Search Websuite to scan PubMed, PMCentral, Journal Hosts and Journal Archives, FullText. Kick-your-searchterm to multiple Engines kick-your-query now !>

A dictionary by aggregated review articles of nephrology, medicine and the life sciences Your one-stop-run pathway from word to the immediate pdf of peer-reviewed on-topic knowledge.

10.1038/onc.2014.67 http://scihub22266oqcxt.onion/10.1038/onc.2014.67 C4175300!4175300 !24662830     free     free     free Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=24662830 &cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 229.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\24662830 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Oncogene 2015 ; 34 (10 ): 1220-30 Nephropedia Template TP {{tp|p=24662830 |t=2015. Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism |pdf=|usr=}}{{24662830 }} gab.com Text Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism JO: Oncogene http://www.kidney.de/pget.php?&tw=1&pmid=24662830 #FOAvip Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394-408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408-422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application. Twit Text FOAVip Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism ????Oncogene http://www.kidney.de/pget.php?&tw=1&pmid=24662830 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=24662830 #FOAvip English Wikipedia <ref>{{Cite pmid|24662830 }}</ref> Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism #MMPMID24662830 Hu CM ; Zhu J ; Guo XE ; Chen W ; Qiu XL ; Ngo B ; Chien R ; Wang YV ; Tsai CY ; Wu G ; Kim Y ; Lopez R ; Chamberlin AR ; Lee EY ; Lee WH Oncogene 2015[Mar]; 34 (10 ): 1220-30 PMID24662830 show ga Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394-408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408-422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application. |Animals [MESH] |Benzamides/chemistry/pharmacology [MESH] |Binding Sites [MESH] |Cell Line, Tumor [MESH] |Cytoskeletal Proteins [MESH] |Disease Models, Animal [MESH] |Disease Progression [MESH] |Gene Expression [MESH] |Heterografts [MESH] |Humans [MESH] |Indoles [MESH] |Inhibitory Concentration 50 [MESH] |Mitosis/drug effects [MESH] |Models, Molecular [MESH] |Molecular Conformation [MESH] |NIMA-Related Kinases [MESH] |Neoplasms/genetics/*metabolism/mortality/*pathology [MESH] |Nuclear Proteins/antagonists & inhibitors/chemistry/genetics/*metabolism [MESH] |Phosphorylation/drug effects [MESH] |Prognosis [MESH] |Protein Binding/drug effects [MESH] |Protein Serine-Threonine Kinases/chemistry/genetics/*metabolism [MESH] |Proteolysis/drug effects [MESH] |Thiazoles/chemistry/pharmacology [MESH]Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor pr(epmc).pdf DeepDyve Pubget Overpricing