Cell Cycle Regulation by TSC2

Understanding how cells control cell growth and cell division is of pivotal importance for the development of treatments for diseases related to cell proliferation, as cancers.  Maintaining homeostasis requires communication between cell growth (mTOR signaling) and cell division (cell cycle regulation), however, the mechanism dictating the link to cell division is unresolved. One of the proteins responsible for the regulation of cell proliferation and cell growth is the protein product of the TSC2 gene, tuberin. Tuberin is known to form the Tuberous Sclerosis Complex (TSC) with the protein product of the TSC1 gene, hamartin, and this complex functions as a tumour suppressor. TSC disease is a devastating form of cancer affecting approximately 1:6000 children that occurs when either TSC1 or TSC2 has been mutated. Considering the severity and the prevalence of this disorder it is alarming that so little research has been done on tuberin and hamartin.

Up to now, it has been demonstrated that the TSC functions as a negative regulator of protein synthesis and cell cycle progression through G1/S. This is because of Tuberin’s GTPase activity that indirectly inhibits the mammalian target of rapamycin (mTOR) pathway. With ample nutrition, Tuberin is inhibited by growth factor signaling, such as Akt/PKB, mTOR is activated, and protein synthesis occurs. Homeostatic regulation over cell size relies on a cell determining when it has reached exactly two times its original volume to trigger cell division.

Our lab has determined that Tuberin also controls the G2/M transition by direct binding to the mitotic CyclinB1 (CycB1) to regulate its subcellular localization and control mitotic onset. This regulation is nutrient-dependent and critical to cell size. We have characterized binding regions on Tuberin and CycB1 and are studying how disruptions to this interaction affect cell growth and division. You can read about our results here and here.

More studies are needed to determine the pivotal steps of Tuberin/CycB1 interaction. Right now, my group is working on the construction of cells lines harbouring clinical tuberin mutations using CRISPR-Cas9 techniques and through a collaboration with the Chemical and Biochemistry Department we are using in silico modeling and alanine scanning to identify specific mutations that can abrogate the interaction of tuberin with its partners, as hamartin and CycB1.


The animal model chosen for our in vivo studies is D. melanogaster as the mammalian Tuberin is 50% homologous with the fly protein; with high conservation in the CycB1 binding domains. Other cellular pathways of interest in my group are Autophagy and DNA damage. Identifying the role of Tuberin in these pathways will open an array of possibility in the treatment of many proliferative diseases.