Tuberin as a Tumor Suppressor and Molecular Integrator of Growth Signaling and Cell Cycle Control

The controlled growth and proliferation of a cell depend on its ability to sense both internal and external conditions and mount appropriate physiological responses. When such regulations go awry, various proliferative diseases may arise, including but not limited to cancers. Central to this control is the cell cycle, a precisely coordinated process that integrates metabolic signals, environmental conditions, and stress responses to maintain cellular homeostasis and ensure proper cell division. The tumour suppressor Tuberin (TSC2) is a key regulator of the cell cycle, yet its role in directly controlling cell proliferation remains poorly understood. Our lab has demonstrated that mitogen and nutrient signaling cascades converge on Tuberin to regulate its interaction with the mitotic cyclin, Cyclin B1 (CCNB1), thereby modulating mitotic entry in a context-dependent manner. Using in vitro ectopic expression and CRISPR/Cas-based approaches, coupled with imaging and cell cycle analysis, we show that weakening Tuberin’s interaction with Cyclin B1—either by altering its phosphorylation status or introducing loss-of-function TSC2 mutations—accelerates mitotic entry, increases proliferation, and leads to aberrant cellular phenotypes. By characterizing Tuberin as a non-canonical regulator of mitotic entry, this research provides new insights into how metabolic signaling influences cell cycle progression. Given the frequent dysregulation of TSC2 in cancer and other proliferative disorders, elucidating this mechanism could reveal novel therapeutic targets for controlling aberrant cell division in disease.