Inca1, short for inhibitor of cyclin-dependent kinase interacting with cyclin A1, is a key regulator in cell cycle control. It functions as a CDK inhibitor, negatively regulating the kinase activity of cyclin-cyclin-dependent kinase complexes, particularly those involving cyclin A1 and CDK2. This regulation is crucial for maintaining normal cell proliferation and preventing uncontrolled cell division, with implications in various biological processes and disease states [2,3].

In Inca1-deficient mice, several phenotypes were observed. In older mice, loss of Inca1 led to an increased number of short-term hematopoietic stem cells, but also enhanced cell cycling upon cytotoxic stress and accelerated bone marrow exhaustion [1]. In leukemia models, Inca1-deficiency severely impaired leukemia induction and maintenance in AML1-ETO9a-induced, MLL-AF9-and c-myc/BCL2-positive leukemia mouse models, indicating distinct functional properties of Inca1 in normal and leukemia-initiating cells [1]. In Inca1(-/-) mice, increased CDK2 activity was seen in the spleen with altered spleen architecture, and Inca1(-/-) embryonic fibroblasts showed an increased fraction of S-phase cells [2].

In conclusion, Inca1 plays a vital role in regulating cell proliferation, especially in hematopoiesis and leukemia. Gene-knockout mouse models have been instrumental in uncovering its functions in these specific disease-related biological processes, highlighting its potential as a target for leukemia therapy.

References:

1. Bäumer, Nicole, Bäumer, Sebastian, Berkenfeld, Frank, Müller-Tidow, Carsten, Tschanter, Petra. 2014. Maintenance of leukemia-initiating cells is regulated by the CDK inhibitor Inca1. In PloS one, 9, e115578. doi:10.1371/journal.pone.0115578. https://pubmed.ncbi.nlm.nih.gov/25525809/

2. Bäumer, Nicole, Tickenbrock, Lara, Tschanter, Petra, Koschmieder, Steffen, Müller-Tidow, Carsten. 2011. Inhibitor of cyclin-dependent kinase (CDK) interacting with cyclin A1 (INCA1) regulates proliferation and is repressed by oncogenic signaling. In The Journal of biological chemistry, 286, 28210-22. doi:10.1074/jbc.M110.203471. https://pubmed.ncbi.nlm.nih.gov/21540187/

3. Diederichs, Sven, Bäumer, Nicole, Ji, Ping, Serve, Hubert, Müller-Tidow, Carsten. 2004. Identification of interaction partners and substrates of the cyclin A1-CDK2 complex. In The Journal of biological chemistry, 279, 33727-41. doi:. https://pubmed.ncbi.nlm.nih.gov/15159402/