Stabilization of GTSE1 by cyclin D1–CDK4/6-mediated phosphorylation promotes cell proliferation with implications for cancer prognosis

• DOI: 10.7554/elife.101075
• Publication Date: 2024-09-20T17:25:10Z
• Authors: Nelson García-Váz...; Tania J González-...; Ethan Lane; Daria Spasskaya; Qingyue Zhang; Marc A Kerzhnerman; YeonTae Jeong; Marta Collu; Daniele Simoneschi; Kelly V Ruggles; Gergely Róna; Sharon Kaisari; Michele Pagano
• Keywords: Cyclin-dependent kinase 6; Retinoblastoma protein; Cyclin D; Cyclin A; Cyclin B

Cyclin D1 is the activating subunit of cell cycle kinases CDK4 and CDK6, its dysregulation a well-known oncogenic driver in many human cancers. The biological function cyclin has been primarily studied by focusing on phosphorylation retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses biochemical experiments, we show that GTSE1 (G2 S phases expressed protein 1), positively regulating progression, previously unknown substrate D1-CDK4/6. mediated D1-CDK4/6 inhibits degradation, leading to high levels also during G1 phase cycle. Functionally, promotes cellular proliferation associated with poor prognosis within pan-cancer cohort. Our findings provide insights into D1’s role control oncogenesis beyond RB phosphorylation.