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468001 occurrences (No.36 in the rank) during 5 years in the PubMed. [no cache] 500 found

172) The HSP90 molecular chaperone plays a key role in the maturation, stability and activation of its clients, including many oncogenic proteins.

--- ABSTRACT ---

PMID:24292678 DOI:10.1038/onc.2013.519

2015 Oncogene

* Restricting direct interaction of CDC37 with HSP90 does not compromise chaperoning of client proteins.

- The HSP90 molecular chaperone plays a key role in the maturation, stability and activation of its clients, including many oncogenic proteins. Kinases are a substantial and important subset of clients requiring the key cochaperone CDC37. We sought an improved understanding of protein kinase chaperoning by CDC37 in cancer cells. CDC37 overexpression in human colon cancer cells increased CDK4 protein levels, which was negated upon CDC37 knockdown. Overexpressing CDC37 increased CDK4 protein half-life and enhanced binding of HSP90 to CDK4, consistent with CDC37 promoting kinase loading onto chaperone complexes. Against expectation, expression of C-terminus-truncated CDC37 (ΔC-CDC37) that lacks HSP90 binding capacity did not affect kinase client expression or activity; moreover, as with wild-type CDC37 overexpression, it augmented CDK4-HSP90 complex formation. However, although truncation blocked binding to HSP90 in cells, ΔC-CDC37 also showed diminished client protein binding and was relatively unstable. CDC37 mutants with single and double point mutations at residues M164 and L205 showed greatly reduced binding to HSP90, but retained association with client kinases. Surprisingly, these mutants phenocopied wild-type CDC37 overexpression by increasing CDK4-HSP90 association and CDK4 protein levels in cells. Furthermore, expression of the mutants was sufficient to protect kinase clients CDK4, CDK6, CRAF and ERBB2 from depletion induced by silencing endogenous CDC37, indicating that CDC37's client stabilising function cannot be inactivated by substantially reducing its direct interaction with HSP90. However, CDC37 could not compensate for loss of HSP90 function, showing that CDC37 and HSP90 have their own distinct and non-redundant roles in maintaining kinase clients. Our data substantiate the important function of CDC37 in chaperoning protein kinases. Furthermore, we demonstrate that CDC37 can stabilise kinase clients by a mechanism that is not dependent on a substantial direct interaction between CDC37 and HSP90, but nevertheless requires HSP90 activity. These results have significant implications for therapeutic targeting of CDC37.

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[frequency of next (right) word to including]

(1)55 the	(10)3 all	(20)2 an	(29)2 lower
(2)28 13	(11)3 cell	(21)2 angiogenesis,	(30)2 lung
(3)11 a	(12)3 our	(22)2 appropriate	(31)2 many
(4)7 those	(13)3 reduced	(23)2 autism	(32)2 questions
(5)5 in	(14)3 their	(24)2 changes	(33)2 studies
(6)5 its	(15)3 three	(25)2 depression,	(34)2 topical
(7)4 2	(17)2 3	(26)2 improved	(35)2 two
(8)4 both	(18)2 37	(27)2 increased
(9)3 age,	(19)2 activated	(28)2 induction

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--- WordNet output for including --- =>含む Overview of verb include The verb include has 4 senses (first 4 from tagged texts) 1. (234) include -- (have as a part, be made up out of; "The list includes the names of many famous writers") 2. (32) include -- (consider as part of something; "I include you in the list of culprits") 3. (18) include -- (add as part of something else; put in as part of a set, group, or category; "We must include this chemical element in the group") 4. (8) admit, let in, include -- (allow participation in or the right to be part of; permit to exercise the rights, functions, and responsibilities of; "admit someone to the profession"; "She was admitted to the New Jersey Bar") --- WordNet end ---