Overturning a cancer dogma: Cyclin D is not tumor activator

Investigators at UC San Diego find that Cyclin D essential to regulating cell cycle progression – the process of cell division and replication – activates a key tumor suppressor, rather than inactivating it as previously thought. The finding fundamentally change the understanding of G1 cell cycle regulation and the molecular origins of many associated cancers.

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The study, published in the journal eLife, completely upend what was thought to be a fundamental knowledge of cell cycle progression in all cancer cells driven by one of the most common genetic pathways mutated in cancer, namely the p16-cyclin D pathway.

Understand the relationship of Cyclin D with cancer

Cyclin D is synthesized during the first stage of cell replication and is believed to help drive the complex and multi-stage process. It involves in interaction with the retinoblastoma (Rb) protein, whose function is to prevent excessive cell growth by inhibiting cell cycle progression until a cell is ready to divide. As shown in relative studies, Rb acts as a tumor suppressor.

However, mutated or dysfunctional Rb is linked with several major cancers and Cyclin D has long been regarded as an oncogene that promotes cancer because it was believed to inactivate the Rb tumor suppressor function through a process called phosphorylation, which involves phosphate molecules being added to proteins, essentially turning them on or off.

Investigators carefully counted the number of phosphates added to Rb during cell cycle progression. There are as many as 14, but the scientists found that cyclin D adds just a single phosphate at one, and only one of the 14 locations essentially make 14 different versions of the Rb tumor suppressor during the early G1 phase. The single phosphate serves to activate Rb, not inactivate it as had been thought for over 20 years.

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