Inhibitor of Cyclin-dependent Kinase (CDK) Interacting with Cyclin A1 (INCA1) regulates proliferation and is repressed by oncogenic signaling
File(s)
Published version
Author(s)
Type
Journal Article
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.
Date Issued
2011-08-12
Date Acceptance
2011-05-01
Citation
Journal of Biological Chemistry, 2011, 286 (32), pp.28210-28222
ISSN
0021-9258
Publisher
Elsevier BV
Start Page
28210
End Page
28222
Journal / Book Title
Journal of Biological Chemistry
Volume
286
Issue
32
Copyright Statement
© 2011 by The American Society for Biochemistry and Molecular Biology, Inc. This is an Open Access article under the CC BY license.
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Publication Status
Published
Date Publish Online
2011-05-03