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Workshop 1: Control of Cell Growth, Division, and Death
(September 29 - October 3, 2003)

Organizers: Jessie Au and Baltazar Aguda

The cell cycle is the sequence of events by which a growing cell replicates all its components and divides them between two daughter cells, so that each daughter receives all the information and machinery necessary to repeat the process. Because cell proliferation underlies all biological growth, development, and reproduction, an understanding of the molecular machinery controlling cell growth and division is a fundamental goal of cell biology. In the past 15 years, there has been an explosion of information about: (1) the genes and proteins that regulate DNA replication, mitosis and cell division (the cell cycle "engine"), and (2) the signal transduction pathways that control the "accelerators and brakes" of the engine. Everyone now agrees that this regulatory network is so complex that rigorous mathematical modeling will be required to understand the intricate relationships among its components, and to derive the observed behavior of proliferating cells to the underlying regulatory system. The purposes of the first workshop of this quarter are to summarize current knowledge about the molecular controls of cell division, to examine the state-of-the-art in computational modeling of these controls, to open a fruitful dialogue between experimental cell biologists and theoreticians, to define the next set of problems to be attacked by mathematical modeling, and to recruit a new generation of collaborative experimentalists and theoreticians to the problem.

The workshop will focus on the cell cycle engine and signal transduction pathways in mammalian cells to set the stage for the next workshop, which will address issues of cancer biology (tumorigenesis, angiogenesis, chemotherapy, drug resistance). The first 2 days will address the mammalian cell cycle engine, as sketched out in a molecular wiring diagram published by Kohn in Molec Biol Cell (10:2703-2734, 1999). Speakers will address the following issues:

• Cyclin-dependent kinases and their partners (cyclins A, B, ...),
• Cyclin-dependent kinase inhibitors (p15, p21, p27),
• Regulation of cell cycle genes expression,
• Cell cycle checkpoints,
• Computational models.

Days 3-5 will focus on the network of signal transduction pathways surrounding the cell cycle engine, as described in a recent review by Hanahan and Weinberg in Cell (100: 57-70, 2000):

• Growth signals (MAP kinase pathway -> cyclin D and pRb),
• Antigrowth signals (TGFb -> Smads -> p15, p21, p27),
• Cell adhesion signals and anoikis (Integrins, Cadherins),
• Survival factors (e.g., IGF1 -> P13K -> NF-kB, FGF -> MEK),
• Cell suicide signals (intrinsic and extrinsic pathways of apoptosis),
• Immortalization (telomerase dynamics),
• Genetic instability (p53 and DNA damage checkpoint).

The mathematical tools that are expected to contribute strongly to these questions are:

• Dynamical systems theory
• Bifurcation theory
• Multiple time scales
• Parameter estimation
• Robust control
• Stochastic differential equations
• Graph theoretic methods

The workshop will bring together experimental cell biologists, theoretical biologists, mathematicians, and computer scientists who are all interested in problems of cell growth, division, and death.