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Author Kharait, Sourabh Prakash
Title Modeling and targeting signal transduction pathways governing cell migration
book jacket
Descript 144 p
Note Source: Dissertation Abstracts International, Volume: 67-06, Section: B, page: 3074
Adviser: Alan Wells
Thesis (Ph.D.)--University of Pittsburgh, 2006
Cell migration is a complex biophysical event that is dysregulated in a variety of human diseases including cancer. The ability of tumor cells to migrate enables cancer dissemination causing significant mortality thus making it an important therapeutic target. Motility is exhibited epigenetically by activation of numerous signaling pathways that transmit extracellular cues to the final effectors of cell movement. Such signaling switches are a part of larger and highly complex signaling (proteomic) networks that are under the control of numerous activators or inhibitors. Although majority of the proteins that are 'required' during cell motility have been identified, it is yet unclear wherein they fit within the signaling network to govern motility. Thus, a 'systems biology' approach is needed to understand the complex interplay of signaling cascades in mediating cell motility so that better therapeutic targets can be defined
We utilized a mathematical modeling approach, called decision tree analysis to map the interplay between five key signaling proteins known to regulate vital biophysical processes of fibroblast motility downstream of EGF receptor activation. Interestingly, our model identified myosin light chain (MLC) mediated cell contractility as a crucial node for maximal motility. Even more non-intuitively the decision tree model predicted that subtotal inhibition of MLC can actually increase motility. Confirmatory experiments with fibroblasts and cancer cells have shown that to be the case
Since the model proposed that total abrogation of contractility can limit cell migration, we asked if such an intervention can limit tumor invasion. Since PKCdelta is implicated in EGF receptor mediated transcellular contractility, we abrogated PKCdelta using pharmacological (Rottlerin) and molecular (RNAi) interventions. Such depletion of PKCdelta reduced migration as well as invasiveness of prostate carcinoma cells predominantly by decreasing their contractility through myosin light chain (MLC). Additionally, activation of PKCdelta correlated with human prostate cancer progression as assessed by immunohistochemistry of prostate tissue sections
In summation our studies illustrate the importance of quantitative (total versus subtotal) disruption of key signaling nodes in mediating a desired cell response. Novel computational modeling approaches are needed to identify newer molecular switches from existing proteomic networks that can be explored, using classical experimental methods, as therapeutic targets
School code: 0178
Host Item Dissertation Abstracts International 67-06B
Subject Biology, Molecular
Health Sciences, Pathology
Biophysics, General
Alt Author University of Pittsburgh
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