Program Leader Thea Tlsty, PhD Program Co-Leader David Toczyski, PhD, FRS

The Cell Cycling and Signaling Program focuses on regulation of cell signaling and of cell cycle control, and how alterations in these processes modulate gene expression, cause mutations, and fuel the steps involved in carcinogenesis.

The cell cycle is the collection of biochemical networks whereby one cell gives rise to two. This entails the coordination of two fundamental programs: cell division, the increase in cell number, encompasses the proper replication and segregation of the genetic material to two daughter cells; cell growth, the increase in cell mass, must be coordinated with division to ensure proper cell size, function, and position.

Superimposed on both of these fundamental programs is the differentiated status of the cell, ranging from stem cell to terminal differentiation. Members of this program study regulated entry into the cell cycle, including proper molecular controls, mechanisms for ensuring fidelity of the processes, and responses to exogenous signals for growth and differentiation. Members also study exit from the cell cycle of both the reversible kind (checkpoint control) and the irreversible kind (senescence and death). Although core components of the cell cycle machinery are common to most cells, the strategy of regulation is often specific to the organism, the tissue, the cell, or the physiological/differentiated state. Multiple aspects of these processes are often controlled by nuclear organization and by signals from the extracellular matrix. Comparison of critical processes between tissues and between species may provide important insights given documented differences in carcinogenic frequency. Observations resulting from basic research in these fundamental processes are applied to clinical questions of diagnosis, prognosis, and prevention of disease, and will ultimately translate into the design of better therapeutic strategies.

The long-term goals of this program are to examine the molecular networks that ensure proper cell cycle progression and proper relation of the cell to its microenvironment, and to use this basic information to identify diagnostic and prognostic markers as well as therapeutic targets for specific organ malignancies. The consequences of the cell-to-cell and cell-to-environment interactions can contribute to misregulation of signaling within tissues and contribute to tumorigenesis. Information produced in this program helps to facilitate understanding of the molecular mechanisms that initiate and allow progression of tumorigenesis.

Areas of research addressed in the Cell Cycling and Signaling Program fall into five broad themes: signals that are sent by the microenvironment to enter the cell cycle; molecular components of the cell cycle engine and its control; physiological consequences of the sum of the signaling pathways; relationships of molecular changes with known phenotypes in the cancer lesion; and application of novel research results to the prevention or control of cancer.

Research undertaken by program members aims to:

• identify control mechanisms in cell cycle regulation and cell signaling that are pivotal in the initiation and progression of cancer;

• identify molecular processes in cell cycle control and cell signaling that are amenable to therapeutic intervention;

• integrate the information that is incoming from the different organ systems for comparing and contrasting basic biology between different tissues and model systems; and

• understand the mechanisms of action of the genes that are identified through the Cancer Center's Cancer Genetics Program with regards to cell cycle control and signaling.