title: Effects of Cyclin Dependent Kinase 9 inhibition on zebrafish larvae.
abstract: CDK9 is a known regulator of cellular transcription, growth and proliferation. Small molecule inhibitors are currently being developed and assessed in clinical trials as anti-cancer drugs. The zebrafish embryo provides an ideal model to explore the effects of CDK9 inhibition in-vivo. This has not been adequately explored previously at the level of a whole organism. We have compared and contrasted the effects of pharmacological and molecular inhibition of CDK9 on somatic growth, apoptosis and cellular proliferation in zebrafish larvae between 0 to 120 hours post fertilisation (hpf) using flavopiridol, a selective CDK9 antagonist, and CDK9-targeting morpholino. We demonstrate that the inhibition of CDK9 diminishes cellular proliferation and increases apoptosis. Subsequently, it affects somatic growth and development of a number of key embryonic structures including the brain, heart, eye and blood vessels. For the first time, we have localized CDK9 at a subcellular level in whole-mounted larvae. This works shows, at a high-throughput level, that CDK9 clearly plays a fundamental role in early cellular growth and proliferation.
authors.affiliation: a British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh , Edinburgh , UK.|b Department of Cardiovascular Sciences , Methodist Hospital Research Institute , Houston , TX , USA.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Matrone
authors.affiliation: a British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh , Edinburgh , UK.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mullins
authors.affiliation: a British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh , Edinburgh , UK.
authors.forename: Carl S
authors.initials: CS
authors.lastname: Tucker
authors.affiliation: a British Heart Foundation Centre for Cardiovascular Science, The Queen's Medical Research Institute, The University of Edinburgh , Edinburgh , UK.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Denvir
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007814:Larva / Q000187:drug effects; D060172:Morpholinos / Q000494:pharmacology; D010641:Phenotype; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016019:Survival Analysis; D015027:Zebrafish / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D060172:Morpholinos; D010880:Piperidines; D047428:Protein Kinase Inhibitors; C077990:alvocidib; D042863:Cyclin-Dependent Kinase 9; D001973:Bromodeoxyuridine
keywords: CDK9; flavopiridol; morpholino; pharmacology; phenotype; zebrafish