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Proc Natl Acad Sci U S A. 2018 Jan 30;115(5):1015-1020. doi: 10.1073/pnas.1711477115. Epub 2018 Jan 16.

Kinase-independent function of E-type cyclins in liver cancer.

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Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
Department of Genetics, Harvard Medical School, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Center for Cancer Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215.
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215.
Department of Biomedical Sciences, Tufts University Veterinary School, North Grafton, MA 01536.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215;


E-type cyclins (cyclins E1 and E2) are components of the core cell cycle machinery and are overexpressed in many human tumor types. E cyclins are thought to drive tumor cell proliferation by activating the cyclin-dependent kinase 2 (CDK2). The cyclin E1 gene represents the site of recurrent integration of the hepatitis B virus in the pathogenesis of hepatocellular carcinoma, and this event is associated with strong up-regulation of cyclin E1 expression. Regardless of the underlying mechanism of tumorigenesis, the majority of liver cancers overexpress E-type cyclins. Here we used conditional cyclin E knockout mice and a liver cancer model to test the requirement for the function of E cyclins in liver tumorigenesis. We show that a ubiquitous, global shutdown of E cyclins did not visibly affect postnatal development or physiology of adult mice. However, an acute ablation of E cyclins halted liver cancer progression. We demonstrated that also human liver cancer cells critically depend on E cyclins for proliferation. In contrast, we found that the function of the cyclin E catalytic partner, CDK2, is dispensable in liver cancer cells. We observed that E cyclins drive proliferation of tumor cells in a CDK2- and kinase-independent mechanism. Our study suggests that compounds which degrade or inhibit cyclin E might represent a highly selective therapeutic strategy for patients with liver cancer, as these compounds would selectively cripple proliferation of tumor cells, while sparing normal tissues.


E-type cyclins; cell cycle; cyclin-dependent kinase CDK2; liver cancer

[Indexed for MEDLINE]
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Conflict of interest statement

Conflict of interest statement: P.S. is a consultant and a recipient of a research grant from Novartis.

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