title: Inhibitor of cyclin-dependent kinase (CDK) interacting with cyclin A1 (INCA1) regulates proliferation and is repressed by oncogenic signaling.
abstract: The cell cycle is driven by the kinase activity of cyclin·cyclin-dependent kinase (CDK) complexes, which is negatively regulated by CDK inhibitor proteins. Recently, we identified INCA1 as an interaction partner and a substrate of cyclin A1 in complex with CDK2. On a functional level, we identified a novel cyclin-binding site in the INCA1 protein. INCA1 inhibited CDK2 activity and cell proliferation. The inhibitory effects depended on the cyclin-interacting domain. Mitogenic and oncogenic signals suppressed INCA1 expression, whereas it was induced by cell cycle arrest. We established a deletional mouse model that showed increased CDK2 activity in spleen with altered spleen architecture in Inca1(-/-) mice. Inca1(-/-) embryonic fibroblasts showed an increase in the fraction of S-phase cells. Furthermore, blasts from acute lymphoid leukemia and acute myeloid leukemia patients expressed significantly reduced INCA1 levels highlighting its relevance for growth control in vivo. Taken together, this study identifies a novel CDK inhibitor with reduced expression in acute myeloid and lymphoid leukemia. The molecular events that control the cell cycle occur in a sequential process to ensure a tight regulation, which is important for the survival of a cell and includes the detection and repair of genetic damage and the prevention of uncontrolled cell division.
authors.affiliation: Department of Medicine, Hematology/Oncology, University ofMvnster, 48129 Münster, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bäumer
authors.forename: Lara
authors.initials: L
authors.lastname: Tickenbrock
authors.forename: Petra
authors.initials: P
authors.lastname: Tschanter
authors.forename: Lisa
authors.initials: L
authors.lastname: Lohmeyer
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bäumer
authors.forename: Boris V
authors.initials: BV
authors.lastname: Skryabin
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Shuchi
authors.initials: S
authors.lastname: Agrawal-Singh
authors.forename: Gabriele
authors.initials: G
authors.lastname: Köhler
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
mesh_terms: D000818:Animals; D001752:Blast Crisis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016196:S Phase; D015398:Signal Transduction
chemical_list: D002352:Carrier Proteins; C492512:INCA1 protein, human; C000603586:Inca1 protein, mouse; D009363:Neoplasm Proteins; D010750:Phosphoproteins; C495894:CDK2 protein, human; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2