2009 Scientific Report

VARI | 2009
Research Interests
The primary focus of the Systems Biology laboratory is identifying and understanding the genes and signaling pathways that,
when mutated, contribute to the pathophysiology of cancer. We take advantage of RNA interference (RNAi) and novel proteomic
approaches to identify the enzymes that control cell growth, proliferation, and survival. For example, after screening the human
genome for more than 600 kinases and 200 phosphatases—called the “kinome” and “phosphatome”, respectively—that act
with chemotherapeutic agents in controlling apoptosis, we identified several essential kinases and phosphatases whose roles
in cell survival were previously unrecognized. We are asking several questions. How are these survival enzymes regulated at
the molecular level? What signaling pathway(s) do they regulate? Does changing the number of enzyme molecules present
inhibit waves of compensatory changes at the cellular level (system-level changes)? What are the system-level changes after
reduction or loss of each gene?
Mitochondrial dysfunction in cancer
Mitochondria are dynamic organelles that house many crucial cellular processes. While mitochondria are best known for
producing more than 90% of cellular ATP and for releasing cytochrome c during apoptosis, they also modulate mitochondrial
dynamics and ion homeostasis, oxidize carbohydrates and fatty acids, and participate in numerous other molecular signaling
pathways. Disruption of mitochondrial function contributes to the etiology of at least fifty diseases, including cancer, underscoring
the importance of identifying the molecular components that regulate normal and pathological function in these organelles.
Similar to the discovery of the BCL-2
Figure 1
family members, which play key roles in
mitochondrial apoptosis, the discovery
of enzymes that regulate mitochondrial
function (cytochrome c release, ATP production,
and fission/fusion) will provide
critical insights into the physiology of
this organelle and how this physiology is
disrupted in cancer.
Figure 1. Mitochondrial dynamics as visualized by MitoTraker staining (red). As an outcome, mitochondrial dysfunction from
a single kinase or phosphatase may have consequences that range from defects in energy metabolism to the etiology of complex
diseases such as cancer. Our preliminary data with a mitochondrial kinase and two different mitochondrial phosphatases demonstrate
that, when lost, the kinase decreases ATP production and drives mitochondrial fusion, while each phosphatase studied leads to an
increase in ATP production. We have data that excessive or even modest increases in ATP levels may completely prevent mitochondrialdependent
apoptosis. The significance of our work is that we have identified the specific mitochondrial signaling proteins that interact in
a complex with key components of the electron transport chain and also with the mitochondrial fission/fusion machinery. Related to this,
we have also identified a mitochondrial-specific kinase that controls the dynamic nature of the mitochondria, specifically mitochondrial
fission and fusion.
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