Details

Autor(en) / Beteiligte

• Geng, Yan
• Michowski, Wojciech
• Chick, Joel M.
• Wang, Yaoyu E.
• Jecrois, M. Emmanuelle
• Sweeney, Katharine E.
• Liu, Lijun
• Han, Richard C.
• Ke, Nan
• Zagozdzon, Agnieszka
• Sicinska, Ewa
• Bronson, Roderick T.
• Gygi, Steven P.
• Sicinski, Piotr

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2018-01, Vol.115 (5), p.1015-1020

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2018

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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 Emight 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.