The tumor suppressor tuberin regulates mitotic onset through the cellular localization of cyclin B1

Tuberous sclerosis is a multi-organ disorder characterized by the formation of benign tumors, called hamartomas, which affect more than 1 million people worldwide. The syndrome is initiated by a mutation in one of two tumor suppressor genes, TSC1 or TSC2 which encode for the proteins hamartin and tuberin, respectively. Herein we demonstrate that tuberin binds and regulates the G(2)/M cyclin, cyclin B1. We have determined that this binding region encompasses a mutational hotspot within tuberin implicated in some of the most severe cases of TS. Mimicking a mutation found in a subset of patients with Tuberous sclerosis we found a significant reduction in the binding between tuberin and cyclin B1. Functionally, our data supports that tuberin plays a role in regulating the cellular localization of cyclin B1. These results demonstrate a novel and clinically relevant mechanism where tuberin functions in mitotic onset