Abstract
AbstractA new approach to the modular, complex systems analysis of nonlinear dynamics in cell cycling network transformations involved in carcinogenesis is proposed. Carcinogenesis is a complex process that involves dynamically inter-connected biomolecules in the intercellular, membrane, cytosolic, nuclear and nucleolar compartments that form numerous inter-related pathways referred to as networks.The variable biotopology of such dynamic networks is highly complex, and has a number of interesting properties that can be formally characterized at one level of organization by mathematical structures called 'biogroupoids'.One such family of pathways contains the cell cyclins. Cyclins are proteins that link several critical pro-apoptotic and other cell cycling/ division components, including the tumor suppressor gene TP53 and its product, the Thomsen-Friedenreich antigen (T antigen), Rb, mdm2, c-Myc, p21, p27, Bax, Bad and Bcl-2, which all play major roles in carcinogenesis of many cancers. A novel theoretical analysis is thus possible based on recently published studies of cyclin signaling, with special emphasis placed on the roles of cyclins D1 and E, suggests novel clinical trials and rational therapies of cancer through reestablishment of cell cycling inhibition in metastatic cancer cells.
Highlights
A new approach to the modular, complex systems analysis of nonlinear dynamics in cell cycling network transformations involved in carcinogenesis is proposed
In human lung tumors and soft tissue sarcomas, it has recently been discovered that cyclin A/cdk2 complex expression and kinase activity were reliable predictors of proliferation and unfavorable prognosis, thereby further substantiating the epidemiological factors of cyclin signaling (Dobashi et al, 2003; Noguchi et al, 2000)
Cells treated with various concentrations of UCN-01 showed decreased pRb phosphorylation in a dose-dependent manner (Chen et al, 1999). These results suggest that CDK2- or CDK4-regulated steps are targets for UCN-01-induced cell-cycle arrest
Summary
Cyclin E1 locus amplification is rare in breast cancer, the protein product is overexpressed in over 40% of breast carcinomas (Loden et al, 2002). Cyclin D1 is predominantly overexpressed in ERC tumors, and cyclin E overexpression is confined to ER¡ tumors (Gillett et al, 1994; Alle et al, 1998; Loden et al, 2002). The overexpression of several cell cycle regulators has been strongly associated with apoptotic-like behavior, as well as frank apoptosis, in cancer cells, which include c-Myc, E2F-1 and HPV. Apoptosis and its connection to cell cycle-related proteins is of interest therapeutically, as these types therapies could lead to the cancer cell annihilation via apoptosis. A shift has occurred, changing the focus of chemotherapy from exploration of agents that cause cell growth arrest to those that favor apoptosis
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