Predicted points of cell-cycle fragility are consistent with known malfunctions in solid and hematological cancers

BIOT 178

Satyaprakash Nayak, sn248@cornell.edu1, Saniya Salim, ss585@cornell.edu2, and Jeffrey D. Varner, jdv27@cornell.edu1. (1) School of Chemical and Biomolecular Engineering, Cornell University, 244 Olin Hall, Cornell University, Ithaca, NY 14853, (2) Department of Biological and Environmental Engineering, Cornell University, 106 Riley-Robb Hall, Cornell University, Ithaca, NY 14853
Cell division or cell cycle is one of the most fundamental and highly regulated processes in biology. Malfunctions in cell cycle, as evidenced by uncontrolled proliferation underlie many cancers. Our working hypothesis is that a single-cell mathematical model of cell-cycle, which mechanistically describes the molecular events controlling cell division, could be used to computationally determine points of network fragility that correspond to known, clinically observed, cell-cycle malfunctions. We analyzed three different published models of cell-cycle progression and compare our computationally identified fragile points with literature. A third-order backward difference scheme was used to solve the sensitivity equations which gave a 3-fold speedup over the traditional finite difference method. The top 15 fragile points matched with clinical observations of malfunctioning points and included global elements like translational efficiency, programmed proteolysis of cyclins by Ubiquitin Proteasome System (UPS), phosphorylation /dephosphorylation of CDC25 in G1/S and synthesis of 14-3-3 sigma proteins in G2/M phase.
 

Emerging Technologies: Systems Biology
8:00 AM-11:00 AM, Wednesday, August 22, 2007 BCEC -- 108, Oral

Division of Biochemical Technology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007