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return kwic search for functional out of >500 occurrences
267449 occurrences (No.100 in the rank) during 5 years in the PubMed. [cache]

232) Here we use a zebrafish model to describe the functional consequences of pVHL loss on the p53/Mdm2 pathway.

--- ABSTRACT ---

PMID:24469044 DOI:10.1038/onc.2013.598

2015 Oncogene

* The von Hippel-Lindau tumor suppressor regulates programmed cell death 5-mediated degradation of Mdm2.

- Functional loss of the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL), which is part of an E3-ubiquitin ligase complex, initiates most inherited and sporadic clear-cell renal cell carcinomas (ccRCC). Genetic inactivation of the TP53 gene in ccRCC is rare, suggesting that an alternate mechanism alleviates the selective pressure for TP53 mutations in ccRCC. Here we use a zebrafish model to describe the functional consequences of pVHL loss on the p53/Mdm2 pathway. We show that p53 is stabilized in the absence of pVHL and becomes hyperstabilized upon DNA damage, which we propose is because of a novel in vivo interaction revealed between human pVHL and a negative regulator of Mdm2, the programmed cell death 5 (PDCD5) protein. PDCD5 is normally localized at the plasma membrane and in the cytoplasm. However, upon hypoxia or loss of pVHL, PDCD5 relocalizes to the nucleus, an event that is coupled to the degradation of Mdm2. Despite the subsequent hyperstabilization and normal transcriptional activity of p53, we find that zebrafish vhl(-/-) cells are still as highly resistant to DNA damage-induced cell cycle arrest and apoptosis as human ccRCC cells. We suggest this is because of a marked increase in expression of birc5a, the zebrafish homolog of Survivin. Accordingly, when we knock down Survivin in human ccRCC cells we are able to restore caspase activity in response to DNA damage. Taken together, our study describes a new mechanism for p53 stabilization through PDCD5 upon hypoxia or pVHL loss, and reveals new clinical potential for the treatment of pathobiological disorders linked to hypoxic stress.

--- ABSTRACT END ---

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(1)50 magnetic	(18)4 gastrointestinal	(35)3 integration	(52)2 connections
(2)38 connectivity	(19)4 outcome	(36)3 interactions	(53)2 differentiation
(3)29 and	(20)4 outcomes	(37)3 movement	(54)2 domains
(4)8 limitations	(21)4 relationships	(38)3 single	(55)2 endurance
(5)7 network	(22)4 unit	(39)3 status	(56)2 health
(6)7 recovery	(23)3 Assessment	(40)3 status,	(57)2 imaging
(7)7 role	(24)3 MRI	(41)3 studies	(58)2 impact
(8)6 changes	(25)3 Well-Being	(42)2 CD133	(59)2 integrity
(9)6 results	(26)3 activation	(43)2 HL	(60)2 losses
(10)5 alterations	(27)3 brain	(44)2 ability	(61)2 networks
(11)5 limitation	(28)3 consequences	(45)2 activity	(62)2 neuronal
(12)5 neuroimaging	(29)3 coupling	(46)2 analyses	(63)2 organization
(13)5 properties	(30)3 decline	(47)2 as	(64)2 parameters
(14)5 theory	(31)3 deficits	(48)2 assays	(65)2 roles
(15)4 capacity	(32)3 differences	(49)2 assessment	(66)2 significance
(16)4 connectivity,	(33)3 impairment	(50)2 characteristics	(67)2 specialization
(17)4 foods	(34)3 improvement	(51)2 cognitive

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--- WordNet output for functional --- =>機能の, 関数の, 機能する, 機能上の, 実用的な, 機能的な Overview of adj functional The adj functional has 6 senses (first 2 from tagged texts) 1. (3) functional -- (designed for or capable of a particular function or use; "a style of writing in which every word is functional"; "functional architecture") 2. (1) functional -- (involving or affecting function rather than physiology; "functional deafness") 3. functional -- (relating to or based on function especially as opposed to structure; "the problem now is not a constitutional one; it is a functional one"; "delegates elected on a functional rather than a geographical basis") 4. functional, usable, useable, operable, operational -- (fit or ready for use or service; "the toaster was still functional even after being dropped"; "the lawnmower is a bit rusty but still usable"; "an operational aircraft"; "the dishwasher is now in working order") 5. functional -- (designed for or adapted to a function or use; "functional education selects knowledge that is concrete and usable rather than abstract and theoretical"; "functional architecture") 6. running, operative, functional, working -- ((of e.g. a machine) performing or capable of performing; "in running (or working) order"; "a functional set of brakes") --- WordNet end ---