Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85714
Title:
Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.
Authors:
Lee, S B; Kim, S H; Bell, D W; Wahrer, D C; Schiripo, T A; Jorczak, M M; Sgroi, D C; Garber, J E; Li, F P; Nichols, K E; Varley, Jennifer; Godwin, A K; Shannon, K M; Harlow, E; Haber, D A
Abstract:
Li Fraumeni Syndrome (LFS) is a multicancer phenotype, most commonly associated with germ-line mutations in TP53. In a kindred with LFS without an inherited TP53 mutation, we have previously reported a truncating mutation (1100delC) in CHK2, encoding a kinase that phosphorylates p53 on Ser(20). Here, we describe a CHK2 missense mutation (R145W) in another LFS family. This mutation destabilizes the encoded protein, reducing its half-life from >120 min to 30 min. This effect is abrogated by treatment of cells with a proteosome inhibitor, suggesting that CHK2(R145W) is targeted through this degradation pathway. Both 1100delC and R145W germ-line mutations in CHK2 are associated with loss of the wild-type allele in the corresponding tumor specimens, and neither tumor harbors a somatic TP53 mutation. Our observations support the functional significance of CHK2 mutations in rare cases of LFS and suggest that such mutations may substitute for inactivation of TP53.
Affiliation:
Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.
Citation:
Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. 2001, 61 (22):8062-7 Cancer Res.
Journal:
Cancer Research
Issue Date:
15-Nov-2001
URI:
http://hdl.handle.net/10541/85714
PubMed ID:
11719428
Type:
Article
Language:
en
ISSN:
0008-5472
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorLee, S Ben
dc.contributor.authorKim, S Hen
dc.contributor.authorBell, D Wen
dc.contributor.authorWahrer, D Cen
dc.contributor.authorSchiripo, T Aen
dc.contributor.authorJorczak, M Men
dc.contributor.authorSgroi, D Cen
dc.contributor.authorGarber, J Een
dc.contributor.authorLi, F Pen
dc.contributor.authorNichols, K Een
dc.contributor.authorVarley, Jenniferen
dc.contributor.authorGodwin, A Ken
dc.contributor.authorShannon, K Men
dc.contributor.authorHarlow, Een
dc.contributor.authorHaber, D Aen
dc.date.accessioned2009-11-10T09:21:59Z-
dc.date.available2009-11-10T09:21:59Z-
dc.date.issued2001-11-15-
dc.identifier.citationDestabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome. 2001, 61 (22):8062-7 Cancer Res.en
dc.identifier.issn0008-5472-
dc.identifier.pmid11719428-
dc.identifier.urihttp://hdl.handle.net/10541/85714-
dc.description.abstractLi Fraumeni Syndrome (LFS) is a multicancer phenotype, most commonly associated with germ-line mutations in TP53. In a kindred with LFS without an inherited TP53 mutation, we have previously reported a truncating mutation (1100delC) in CHK2, encoding a kinase that phosphorylates p53 on Ser(20). Here, we describe a CHK2 missense mutation (R145W) in another LFS family. This mutation destabilizes the encoded protein, reducing its half-life from >120 min to 30 min. This effect is abrogated by treatment of cells with a proteosome inhibitor, suggesting that CHK2(R145W) is targeted through this degradation pathway. Both 1100delC and R145W germ-line mutations in CHK2 are associated with loss of the wild-type allele in the corresponding tumor specimens, and neither tumor harbors a somatic TP53 mutation. Our observations support the functional significance of CHK2 mutations in rare cases of LFS and suggest that such mutations may substitute for inactivation of TP53.en
dc.language.isoenen
dc.subjectColonic Canceren
dc.subjectCancerous Gene Expression Regulationen
dc.subjectCultured Tumour Cellsen
dc.subject.meshAdult-
dc.subject.meshBase Sequence-
dc.subject.meshColonic Neoplasms-
dc.subject.meshDNA, Complementary-
dc.subject.meshFemale-
dc.subject.meshGene Expression Regulation, Neoplastic-
dc.subject.meshGene Silencing-
dc.subject.meshGenes, p53-
dc.subject.meshHumans-
dc.subject.meshLi-Fraumeni Syndrome-
dc.subject.meshLoss of Heterozygosity-
dc.subject.meshMale-
dc.subject.meshMolecular Sequence Data-
dc.subject.meshMutation, Missense-
dc.subject.meshPedigree-
dc.subject.meshProtein Kinases-
dc.subject.meshProtein-Serine-Threonine Kinases-
dc.subject.meshTumor Cells, Cultured-
dc.titleDestabilization of CHK2 by a missense mutation associated with Li-Fraumeni Syndrome.en
dc.typeArticleen
dc.contributor.departmentMassachusetts General Hospital Cancer Center and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA.en
dc.identifier.journalCancer Researchen

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