Auld, Douglas, Jenkins, Jeremy and Concannon, John (2021) Cell size homeostasis is maintained by a circuitry involving a CDK4-determined target size that programs the cell size-dependent activation of p38. Developmental cell. ISSN 1878-1551

Abstract

While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for each of the different cell types. In 1975, Hartwell and Nurse suggested that in eukaryotes, cell size is determined by size checkpoints – mechanisms that restrict cell cycle progression of cells that are smaller than their target size. Curiously, such checkpoint mechanisms imply a conceptual distinction between a cell’s actual size and its target size. In the present study, we materialize this distinction by describing experimental assays that discriminately quantify the target size value of cells. With these assays, we show that a cell’s size and target size are distinct phenotypes that are dictated by different upstream regulators. While mTORC1 promotes growth in cell size, our data suggests that a cell’s target size value is regulated by other pathways including CDK4. For example, while rapamycin (an mTORC1 inhibitor) decreases cell size, it does not change the target size that is required for the G1/S transition. The CDK4-cyclinD1/Rb pathway has previously been proposed to regulate target size. Yet, in lacking experimental means that discriminate perturbations of cell growth from perturbations that reprogram target size, such claims on target size have not been validated. To investigate the functions of CDK4 in target size determination, we used genetic and chemical means to dial higher and lower levels of CDK4 activity. These measurements identified roles of CDK4 on target size determination that are distinct from other G1 CDKs. CDK4 activity shifts the target size threshold below which inappropriately small cells exhibit elevated p38 activity. Using C. elegans, we show that these influences of CDK4 on size determination also function in vivo. Our data support a model where mTORC1, p38, and CDK4 cooperate in a manner analogous to the function of a thermostat. While mTORC1 promotes cellular growth as prompted by p38, CDK4 is analogous to the thermostat dial that sets the critical target size associated with cell size homeostasis.

Item Type:	Article
Date Deposited:	06 Jul 2021 00:45
Last Modified:	06 Jul 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44375