TY - JOUR
T1 - CDK6 kinase activity is required for thymocyte development
AU - Hu, Miaofen G.
AU - Deshpande, Amit
AU - Schlichting, Nicolette
AU - Hinds, Elisabeth A.
AU - Mao, Changchuin
AU - Dose, Marei
AU - Hu, Guo Fu
AU - Van Etten, Richard A.
AU - Gounari, Fotini
AU - Hinds, Philip W.
PY - 2011/6/9
Y1 - 2011/6/9
N2 - 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 (Cdk6K43M) 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 Cdk6R31C 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 Notchdependent 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 Cdk6K43M mice rescued most defects observed inyoungmice. 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 identifiesCDK6kinase activity as a potential therapeutic target inhumanlymphoid malignancies.
AB - 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 (Cdk6K43M) 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 Cdk6R31C 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 Notchdependent 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 Cdk6K43M mice rescued most defects observed inyoungmice. 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 identifiesCDK6kinase activity as a potential therapeutic target inhumanlymphoid malignancies.
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U2 - 10.1182/blood-2010-08-300517
DO - 10.1182/blood-2010-08-300517
M3 - Article
C2 - 21508411
AN - SCOPUS:79959399059
SN - 0006-4971
VL - 117
SP - 6120
EP - 6131
JO - Blood
JF - Blood
IS - 23
ER -