title: Genetic inactivation of Cdk7 leads to cell cycle arrest and induces premature aging due to adult stem cell exhaustion.
abstract: Cyclin-dependent kinase (Cdk)7, the catalytic subunit of the Cdk-activating kinase (CAK) complex has been implicated in the control of cell cycle progression and of RNA polymerase II (RNA pol II)-mediated transcription. Genetic inactivation of the Cdk7 locus revealed that whereas Cdk7 is completely dispensable for global transcription, is essential for the cell cycle via phosphorylation of Cdk1 and Cdk2. In vivo, Cdk7 is also indispensable for cell proliferation except during the initial stages of embryonic development. Interestingly, widespread elimination of Cdk7 in adult tissues with low proliferative indexes had no phenotypic consequences. However, ablation of conditional Cdk7 alleles in tissues with elevated cellular turnover led to the efficient repopulation of these tissues with Cdk7-expressing cells most likely derived from adult stem cells that may have escaped the inactivation of their targeted Cdk7 alleles. This process, a physiological attempt to maintain tissue homeostasis, led to the attrition of adult stem cell pools and to the appearance of age-related phenotypes, including telomere shortening and early death.
authors.affiliation: Experimental Oncology, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Ganuza
authors.forename: Cristina
authors.initials: C
authors.lastname: Sáiz-Ladera
authors.forename: Marta
authors.initials: M
authors.lastname: Cañamero
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gómez
authors.forename: Ralph
authors.initials: R
authors.lastname: Schneider
authors.forename: María A
authors.initials: MA
authors.lastname: Blasco
authors.forename: David
authors.initials: D
authors.lastname: Pisano
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
authors.forename: David
authors.initials: D
authors.lastname: Santamaría
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D019588:Aging, Premature / Q000235:genetics*; D000818:Animals; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000502:physiology*; D047108:Embryonic Development / Q000502:physiology; D005260:Female; D006706:Homeostasis / Q000502:physiology; D051379:Mice; D059506:Telomere Shortening / Q000502:physiology
chemical_list: D018844:Cyclin-Dependent Kinases; C090586:Cdk7 protein, mouse