ELIZA

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290904 occurrences (No.84 in the rank) during 5 years in the PubMed. [no cache] 500 found

208) 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.

--- 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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(1)66 the	(12)4 activity	(24)2 among	(35)2 interhemispheric
(2)30 in	(13)4 both	(25)2 availability	(36)2 it
(3)23 by	(14)4 cell	(26)2 blood	(37)2 likelihood
(4)13 null	(16)3 ability	(27)2 but	(38)2 number
(5)13 to	(17)3 after	(28)2 compared	(39)2 rates
(6)10 glutathione	(18)3 binding	(29)2 effortful	(40)2 stem
(7)8 and	(19)3 or	(30)2 ejection	(41)2 total
(8)8 expression	(20)3 risk	(31)2 following	(42)2 tumor
(9)5 levels	(21)3 sensitivity	(32)2 from	(43)2 which
(10)5 significantly	(22)2 (P	(33)2 glutathione,
(11)4 PGE2	(23)2 BRCA-1	(34)2 hippocampal

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--- WordNet output for reduced --- =>貧しい暮らし, 落ちぶれた生活 Overview of verb reduce The verb reduce has 20 senses (first 11 from tagged texts) 1. (102) reduce, cut down, cut back, trim, trim down, trim back, cut, bring down -- (cut down on; make a reduction in; "reduce your daily fat intake"; "The employer wants to cut back health benefits") 2. (9) reduce -- (make less complex; "reduce a problem to a single question") 3. (5) reduce -- (bring to humbler or weaker state or condition; "He reduced the population to slavery") 4. (3) reduce -- (simplify the form of a mathematical equation of expression by substituting one term for another) 5. (3) reduce -- (lower in grade or rank or force somebody into an undignified situation; "She reduced her niece to a servant") 6. (3) reduce, come down, boil down -- (be the essential element; "The proposal boils down to a compromise") 7. (2) shrink, reduce -- (reduce in size; reduce physically; "Hot water will shrink the sweater"; "Can you shrink this image?") 8. (1) reduce -- (lessen and make more modest; "reduce one's standard of living") 9. (1) reduce, scale down -- (make smaller; "reduce an image") 10. (1) deoxidize, deoxidise, reduce -- (to remove oxygen from a compound, or cause to react with hydrogen or form a hydride, or to undergo an increase in the number of electrons) 11. (1) reduce, tighten -- (narrow or limit; "reduce the influx of foreigners") 12. repress, quash, keep down, subdue, subjugate, reduce -- (put down by force or intimidation; "The government quashes any attempt of an uprising"; "China keeps down her dissidents very efficiently"; "The rich landowners subjugated the peasants working the land") 13. reduce -- (undergo meiosis; "The cells reduce") 14. reduce -- (reposition (a broken bone after surgery) back to its normal site) 15. reduce -- (destress and thus weaken a sound when pronouncing it) 16. abridge, foreshorten, abbreviate, shorten, cut, contract, reduce -- (reduce in scope while retaining essential elements; "The manuscript must be shortened") 17. boil down, reduce, decoct, concentrate -- (be cooked until very little liquid is left; "The sauce should reduce to one cup") 18. reduce, boil down, concentrate -- (cook until very little liquid is left; "The cook reduced the sauce by boiling it for a long time") 19. dilute, thin, thin out, reduce, cut -- (lessen the strength or flavor of a solution or mixture; "cut bourbon") 20. reduce, melt off, lose weight, slim, slenderize, thin, slim down -- (take off weight) Overview of adj reduced The adj reduced has 2 senses (first 2 from tagged texts) 1. (6) decreased, reduced -- (made less in size or amount or degree) 2. (1) reduced, rock-bottom -- (well below normal (especially in price)) --- WordNet end ---