title: CDK6 kinase activity is required for thymocyte development.
abstract: 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.
authors.affiliation: Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: Miaofen G
authors.initials: MG
authors.lastname: Hu
authors.forename: Amit
authors.initials: A
authors.lastname: Deshpande
authors.forename: Nicolette
authors.initials: N
authors.lastname: Schlichting
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Hinds
authors.forename: Changchuin
authors.initials: C
authors.lastname: Mao
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.forename: Guo-Fu
authors.initials: GF
authors.lastname: Hu
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
authors.forename: Philip W
authors.initials: PW
authors.lastname: Hinds
mesh_terms: D000483:Alleles; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D051361:Cyclin-Dependent Kinase 6 / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D055879:Gene Knock-In Techniques; D019337:Hematologic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013950:Thymus Gland / Q000201:enzymology*
chemical_list: D053645:Interleukin-2 Receptor alpha Subunit; D051880:Receptors, Notch; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6