The role of p16INK4a in cellular senescence caused by mitotic stress after loss of Lin9

• Applicant: Professor Dr. Stefan Gaubatz
• Subject Area: Cell Biology
• Term: from 2010 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 175758103

p16INK4a is a cell cycle inhibitor that is expressed at high levels in senescent cells. p16INK4a contributes to physiological aging and it is an important tumor suppressor that is inactivated in a large number of human cancers. However, the pathways that activate p16INK4a during aging, in response to oncogenes and by other cellular stresses are still poorly understood. We have recently identified LINC, a novel E2F/ pocket protein complex in mammalian cells. LINC consist of a core module of five proteins and dynamically associates with E2Fs, pocket proteins and the B-MYB transcription factor during the cell cycle. We found that conditional deletion of Lin9, a core subunit of LINC, severely abolishes the ability of cells to proliferate and to progress through mitosis. This mitotic stress eventually leads to activation of p16INk4a and cellular senescence. Deletion of Lin9 in adult mice in vivo results in inhibition of proliferation and tissue atrophy. In this proposal we will address the contribution of p16INK4a to the Lin9-mutant phenotype in vitro and in vivo. Secondly, we will investigate how p16INK4a is activated after loss of Lin9. These experiments will provide insights into the pathways that lead to senescence after mitotic stress. The pathways that induce senescence and activate p16INK4a are relevant for cancer research and stem cell research.

• DFG Programme: Research Grants