Linked Life Data

21508411

Source:http://linkedlifedata.com/resource/pubmed/id/21508411

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
23
pubmed:dateCreated
2011-6-10
pubmed:abstractText
Cyclin-dependent kinase-6 (CDK6) is required for early thymocyte development and tumorigenesis. To mechanistically dissect the role of CDK6 in thymocyte development, we generated and analyzed mutant knock-in mice and found that mice expressing a kinase-dead Cdk6 allele (Cdk6(K43M)) had a pronounced reduction in thymocytes and hematopoietic stem cells and progenitor cells (Lin?Sca-1?c-Kit? [LSK]). In contrast, mice expressing the INK4-insensitive, hyperactive Cdk6(R31C) allele displayed excess proliferation in LSK and thymocytes. However, this is countered at least in part by increased apoptosis, which may limit progenitor and thymocyte expansion in the absence of other genetic events. Our mechanistic studies demonstrate that CDK6 kinase activity contributes to Notch signaling because inactive CDK6 kinase disrupts Notch-dependent survival, proliferation, and differentiation of LSK, with concomitant alteration of Notch target gene expression, such as massive up-regulation of CD25. Further, knockout of CD25 in Cdk6(K43M) mice rescued most defects observed in young mice. These results illustrate an important role for CDK6 kinase activity in thymocyte development that operates partially through modulating Notch target gene expression. This role of CDK6 as a downstream mediator of Notch identifies CDK6 kinase activity as a potential therapeutic target in human lymphoid malignancies.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1528-0020
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
117
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
6120-31
pubmed:dateRevised
2011-11-10
pubmed:meshHeading
pubmed:year
2011
pubmed:articleTitle
CDK6 kinase activity is required for thymocyte development.
pubmed:affiliation
Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural