DESCRIPTION (provided by applicant): The mechanisms that control cell growth and size are largely unknown and represent a fundamental unsolved problem in biology. We recently discovered a checkpoint that links mitotic entry to membrane growth. Our analysis of this checkpoint suggests a novel hypothesis: we propose that vesicles arriving at a site of membrane growth generate a checkpoint signal that is proportional to the extent of membrane growth. We further hypothesize that downstream components read the strength of this signal to determine when sufficient growth has occurred for entry into mitosis. This hypothesis suggests a simple and broadly relevant solution to two fundamental problems in cell biology: 1) How is cell size controlled? And 2) how is membrane growth integrated with the cell cycle? The proposed Aims test key predictions of the hypothesis. Aim 1 uses diverse approaches, including single cell analysis, to test whether membrane growth is translated into a proportional checkpoint signal. Aim 2 tests whether key checkpoint components translate a gradually increasing checkpoint signal into a switch-like output that triggers mitosis. Completion of the Aims will define a novel checkpoint mechanism that could control the size and shape of all eukaryotic cells.

PUBLIC HEALTH RELEVANCE: Severe defects in cell size and shape are a nearly universal feature of cancer cells and have long been a basis of cancer pathology in the clinic. These defects may define a difference from normal cells that could be exploited to selectively kill cancer cells. To explore this novel idea, we need a better understanding of the mechanisms that control growth and size and how they go wrong in cancer cells.