Current Research Interests
M1 metalloprotease regulation of the cell cycle/division
The M1 family of zinc metallopeptidases is characterized by the zinc binding motif HEXXH and an exopeptidase motif GXMXN, additionally endopeptidase activity may be present in some members. In animals, M1 aminopeptidases have been shown to play roles in meiosis and mitosis. Aminopeptidase M1 (APM1) is a single copy gene in Arabidopsis and the mutants are haplo-insufficient. APM1 loss-of-functions mutants show distinct developmental defects in embryogenesis and seedling development. We were able to separate APM1 embryonic and seedling functions by using inducible silencing (artificial microRNA) of APM1 in wild type at different stages to phenocopy the mutant defects and inducible expression of APM1 in the mutant to rescue the defects. Using this inducible system we can manipulate the timing of the cell cycle events and elucidate the role of APM1 in cell cycle/division regulation.
We are currently focusing on the enzymatic targets of APM1 activity in addition to protein targets that interact with the C-terminus of APM1, which may have cellular trafficking or regulatory roles.
Flavonoids are poylyphenolic compounds that are important flavor and color constituents of plant-based foods. Flavonoids are signalling molecules within the plant, between the plant and other organisms (e.g., nod gene induction in rhizobacteria), and within other organisms. For example, flavonoids are phytoestrogens and act as mild estrogens in humans. Flavonoid accumulation in the plant is tissue-specific. Aglycone flavonols are associated with the plasma membrane and endomembranes, and plasmadesmata.
Targets of flavonoid signalling
Flavonoids are antioxidants and scavenge reactive oxygen species (ROS) thereby potentially regulating the pathways induced by ROS. Flavonoids are also kinase and phosphatase inhibitors. As such, they can modulate signal transduction within the cell. Likely targets are PTEN, PID, RCN1 (PP2a), and ABCBs. A major target of ROS is PTEN, a tumor suppressor implicated in breast cancer. Flavonoids (like xanthohumol from hop) can reduce stimulate PTEN and reduce tumor proliferation.
Flavonoids and Human Health
Flavonoid regulation of ABCBs and M1 metalloproteinases
Flavonoids are compounds that are produced by all plants, and there are hundreds of different kinds. Flavonoids are part of our daily lives, and we mostly notice of them when we see purple grapes, red roses, or Indian corn, and they are also important flavor components of tea, coffee, wine and chocolate. Flavonoid consumption improves human health; for example, dark (not milk) chocolate (1 oz) has also been shown to be an important antioxidant and helps maintain intestinal health. Identification of flavonoids that have activity and elucidating the mode of action will lead to enhanced therapies for those with poor health.
ATP Binding Cassette family B (ABCB) transporters are involved in pumping chemotherapeutic drugs out of cells in human cancer patients. Cancer cells have more ABCBs than healthy cells. In order for chemotherapy drugs to be effective, the drugs must stay within the cancer cells. Flavonoids inhibit the activity of ABCBs, so more of the drug stays in the cells. This decreases the effective dose of chemotherapy drugs given to a patient, thereby reducing the adverse effects of the drugs on the patient. Co-therapies with either flavonoid-rich whole foods, specific flavonoids alone or drugs based on sites of flavonoid activity on the ABCB are being developed. For example, cancer patients undergoing chemotherapy may be instructed to drink grapefruit juice (hesperidin is the active flavonoid) prior to their treatment; however, consumption of grapefruit juice is contraindicated for some drug treatments. The flavonoid EGCG (epigallocatechin gallate) from green tea also modulates ABCB activity, reverses ABCB drug resistance, and reduces ABCB gene expression.
Flavonoids also inhibit M1 metallopeptidase activity. Flavonoids have been shown to have strong anti-angiogenic properties, and in a series of studies, certain flavonoids were shown to bind reversibly to the human M1 homologue catalytic site without toxicity.
Flavonoid/hormone interactions with reactive oxygen species signaling
Hundreds of different flavonoids are produced by plants, and flavonoids are important flavor and color components of the plant-based food we eat. Flavonoids are phytoestrogens and are active compounds, and flavonoid consumption improves human health and may act as protectants against breast cancer.
One of the best known activities of flavonoids is their antioxidant activity as they scavenge reactive oxygen species (ROS). ROS can act as a signal within the cell and the ROS-induced pathway can produce cell damage and disease, most likely through activating/deactivating kinases/phosphatases. Flavonoids scavenge ROS and can potentially regulate the pathways induced by ROS to reduced damage, as flavonoids potent kinase inhibitors. A major target of ROS is PTEN (phosphatase and tensin homolog) that has been implicated in breast cancer. PTEN is a tumor suppressor, but is inactivated in some forms of breast cancer. Flavonoids (like xanthohumol from hop) can reduce the proliferation of breast cancer cells and stimulate PTEN. Food-based flavonoids are also anti-inflammatory and are an alternative to prescription non-steroidal anti-inflammatory drugs.
Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.