A fundamental problem in biology is how the proper size of an organism is achieved. The size of tissues and organs is a consequence of both cell size and number and is controlled by both extrinsic signals, such as insulin peptides, and intrinsic cell signals that measure nutritional and environmental inputs. This research program will exploit a genetic model organism to understand how cell division is balanced by cell growth by the action of a gene named Tribbles. Tribbles is found in all animals, and in humans it has been connected to cancer and Type 2 diabetes, but its functions are poorly understood. It has been shown that Tribbles blocks: (1) cell division by binding the protein Cdc25, a key trigger of division, and (2) insulin-stimulated cell growth by binding the protein Akt kinase. This research program will shed light on the functions of Tribbles that regulate animal size during development, and will have implications for scientists studying the role of Tribbles in human disease. The research program will also support ongoing efforts to train students in molecular and cell biological approaches to dissect conserved developmental mechanisms in a model organism.
These studies of the conserved role of Trbl in cell growth and proliferation will offer insight into the genetic basis of animal diversity, the mechanism of evolution, the effect of environmental conditions on a developmental program, and the underlying causes of developmental aberrations and metabolic disease. Body sizes vary impressively between closely related animal species, and species-specific adaptations, such as the mammalian forelimb and specialized head segments among insects, show incredible size scaling. Size is subject to intense evolutionary selection pressure with consequences for mate selection, predation and tolerance to environmental changes, moreover animals adjust size to both nutrient availability and a host of environmental cues including temperature and O2 levels. The mechanisms coordinating this developmental plasticity are incompletely understood, and include integration of cues from hormonal signals, growth factors and insulin-like peptides to ensure that energy expended on growth matches energy intake. The kinase Tribbles (Trbl) binds and blocks a number of key targets that regulate cell growth, division and differentiation, notably cdc25 phosphatase to inhibit cell proliferation and Akt kinase to inhibit insulin-stimulated cell growth and metabolism. The notion that Trbl is an conserved adaptor protein that regulates both cell proliferation (by binding and degrading Cdc25) and cell size (by binding and inhibiting Akt) in response to diet will be tested in three aims: (1) to explore the role of Trbl in cell growth during normal and dietary stress; (2) to perform a structure/function analysis of Trbl, focused on its conserved features; and (3) to conduct a screen for proteins that physically interact with Trbl by (a) yeast two hybrid screens and (b) co-immuno-pulldown using Trbl-specific antisera.
