Control of Cell Growth and Proliferation Douglas Kellogg, MCD Biology The Kellogg laboratory investigates fundamental molecular mechanisms that coordinate cell growth and cell division. Analysis of such mechanisms can lead to the identification of new targets for anti-cancer drugs.

	Wild type yeast cells
	The mutant cells above fail to properly coordinate cell growth and cell division

The diverse morphologies and sizes of individual cells and multicellular organisms are generated by highly coordinated patterns of cell growth and cell division. The primary research goal of Kellogg and his colleauges is to understand the molecular mechanisms that coordinate cell growth and cell division. Analysis of these processes can also lead to the identification of new targets for drugs aimed at blocking the growth or proliferation of cancer cells. In addition, Kellogg hopes to gain a better understanding of the molecular mechanisms that generate the extraordinarily diverse forms of life.

Coordination of Cell
Growth and Cell Division

Cells show extraordinary diversity in size. The molecular mechanisms underlying control of cell size are likely to be complex and dynamic, since single-celled organisms are able to maintain the same size over widely varying conditions. In addition, multicellular organisms are composed of cells of many different sizes and include cells that are able to grow without dividing (e.g. oocytes), and others that are able to divide without growing (e.g. fertilized embryos). The molecular mechanisms by which cells sense and maintain size are largely unknown.

Maintenance of a specific cell size requires coordination of cell growth and cell division. In fission yeast, the Wee1 and Cdc25 proteins play critical roles in coordinating cell growth and cell division at the G2/M transition. Loss of Wee1 function causes cells to undergo premature entry into mitosis before sufficient growth has occurred, leading to formation of abnormally small cells. Conversely, loss of Cdc25 function causes delayed entry into mitosis, leading to growth of abnormally large cells. Wee1 is a protein kinase that phosphorylates and inhibits the cyclin-dependent kinase (Cdk) that drives cells into mitosis, thereby preventing entry into mitosis until cells reach a critical size. Cdc25 is a phosphatase that removes the inhibitory phosphate added by Wee1, thereby promoting entry into mitosis. One of the challenges facing scientists in this field is to determine the specific molecular mechanisms that sense cell size and relay this information to Wee1 and Cdc25.

An Intricate Signaling Pathway Coordinates Cell Growth and Cell Division

Kellogg and his colleagues are studying an intricate signaling network that is required for proper coordination of cell growth and cell division. Loss of function of any of the proteins that function in this network can cause cell growth to continue during a prolonged G2 delay, leading to the growth of highly elongated cells that are significantly larger than wild type cells (see figure). Genetic and biochemical data demonstrate that Wee1 is a major target of the signaling network. Interestingly, however, a number of the proteins that regulate Wee1 also appear to be regulated by Cdk activity, suggesting the existence of intricate feedback loops that coordinate cell size and entry into mitosis.

Most of the proteins that function in the signaling network have been highly conserved, indicating that similar networks are likely to function in all eukaryotic cells. The Kellogg laboratory is currently using genetics and biochemistry to understand the function and regulation of the proteins that function in this signaling network. A major focus of their work is to determine how cells sense and regulate cell size. Analysis of the basic biological mechanisms that govern cell growth and cell division promise to advance biomedical strategies, such as the identification of new targets for drugs aimed at blocking the growth or proliferation of cancer cells. Once Kellogg's group gains a better understanding of the fundamental mechanisms that control cell size, they hope to also investigate how these mechanisms are modified in different species to generate the diverse forms of life.