Garcia-Vazquez, N.; Gonzalez-Robles, T. J.; Lane, E.; Spasskaya, D.; Zhang, Q.; Kerzhnerman, M. A.; Jeong, Y.; Collu, M.; Simoneschi, D.; Ruggles, K. V.; Rona, G.; Pagano, M.; Kaisari, S.

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