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Graduate studentships are available.

Undergraduate independent study and senior thesis projects are available.

 

Current Research Interests

Flavonoid Signaling

Figure 9

Flavonoids are poylyphenolic compounds that are important flavor and color c onstituents of plant-based foods. Flavonoids are signaling molecules within the plant, between the plant and other organisms (nod gene induction in rhizobacteria), and within other organisms. For example, flavonoids are phytoestrogens and act as mild estrogens in humans.


Figure 10

Flavonoid accumulation in the plant is tissue-specific. Aglycone flavonols are associated with the PM and endomembranes. They act as autocrine effectors within the cells they are synthesized, but may also act as paracrine effectors in adjacent cells, as flavonols appear to be at plasmadesmata. (Murphy et al., 2000; Peer & Murphy, 2005)


Targets

Flavonoids are antioxidants 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 PGPs. 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 IAA

Figure 12 Figure 11

IAA treatment induces ROS in Arabidopsis roots. In the absence of flavonoids (tt4), more ROS fluorescence is observed but decreased ROS fluorescence if excess flavonols are present (tt3), due to flavonoid anti-oxidant activity. Flavonol accumulation also occurs after IAA treatment; IAA catabolism induces ROS. A modest increase in flavonols is observed after a modest increase in IAA, but after NPA treatment, which increases the amount of IAA in cells, flavonol accumulation is significantly increased. Flavonols also modulate auxin transport (Peer et al., 2004; Peer & Murphy, 2005)

 

Flavonoids and Human Health


Flavonoid regulation of MDR/PGPs 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.

Multiple Drug-Resistance/P-glycoproteins (MDR/PGPs) are transporters that are involved in pumping chemotherapeutic drugs out of cells in human cancer patients. Cancer cells have more MDR/PGPs than healthy cells. In order for chemotherapy drugs to be effective, the drugs must stay within the cancer cells. Flavonoids inhibit the activity of MDR/PGPs, 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 MDR/PGPs 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 MDR/PGP activity, reverses MDR/PGP drug resistance, and reduces MDR/PGP gene expression.

Flavonoids also modulate the uptake of other flavonoids.

Loss of traditional diets rich in flavonoids and other nutrients among Americans has contributed to the rise of type II diabetes and obesity. M1 metalloproteinases are involved in intracellular trafficking of proteins related to type II diabetes, and they are also involved in sterol (fat) uptake into intestinal cells. Flavonoids have been shown to inhibit both the activity of the M1 proteinases and to modulate intracellular trafficking. Therefore, flavonoid-based therapies and a return to traditional diets can help reduce the incidence of type II diabetes and obesity. The use of herbicides on our food has been linked to cancer. M1 proteinase activity in food crops reduces the toxicity of the herbicide to the plants, but can increase the carcinogenicity of the herbicides to humans.


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.


Selected Publications

Blakeslee JJ, Bandyopadhyay A, Lee OR, Mravec J, Sauer M, Titapiwatanakun B, Makam SN, Cheng Y, Bouchard R, Adamec J, Geisler M, Nagashima A, Sakai T, Martinoia E, Friml J, Peer WA, Murphy AS (2007) Interactions among PIN and PGP auxin transporters in Arabidopsis Plant Cell. 2007 Jan 19; [Epub ahead of print] PDF Suppl. data

Carrera E, Holman T, Medhurst A, Peer WA, Schmuths H, Footitt S, Baker A, Theodoulou FK, Holdsworth MJ. (2007). The ABC transporter COMATOSE regulates the seed transcriptome late in phase II of germination. Plant Physiol, in press. PDF

Bandyopadhyay A, Blakeslee JJ, Lee OR, Mravec J, Sauer M, Titapiwatanakun B, Makam SN, Bouchard R, Geisler M, Martinoia E, Friml J, Peer WA, Murphy AS (2007) Interactions of PIN and PGP auxin transport mechanisms. Intercellular Signalling in Plants. Biochemical Society Transactions 35: 137-141. PDF

Orlova I, Marshall-Colon A, Schnepp J, Wood B, Varbanova M, Fridman E, Blakeslee JJ, Peer WA, Murphy AS, Rhodes D, Pichersky E, Dudareva N. (2006) Reduction of Benzenoid Synthesis in Petunia Flowers Reveals Multiple Pathways to Benzoic Acid and Enhancement in Auxin Transport. Plant Cell. 2006 Dec 28; [Epub ahead of print] PDF

Peer WA, Mahmoudian M, Freeman JL, Lahner B, Richards EL, Reeves RD, Murphy AS, Salt DE. (2006) Assessment of plants from the Brassicaceae family as genetic models for the study of nickel and zinc hyperaccumulation. New Phytol. 172: 248-260. PDF

Blakeslee JJ, Bandyopadhyay A, Lee OR, Sauer M, Mravec J, Titapiwatanakun B, Makam S, Bouchard R, Adamec J, Geisler M, Martinoia E, Friml J, Peer WA, Murphy AS (2006) Interactions between PGP, PIN, and AUX/LAX auxin transport proteins from Arabidopsis. Plant Growth Regulation Society of America PDF

Terasaka K, Blakeslee JJ, Titapiwatanakun B, Peer WA, Bandyopadhyay A, Makam SN, Lee OR, Richards EL, Murphy AS, Sato F, Yazaki K (2005) PGP4, an ATP-binding cassette P-glycoprotein, catalyzes auxin transport in Arabidopsis thaliana roots. Plant Cell 17: 2922-2939. PDF Suppl. data

Li J, Yang H, Peer WA, Richter G, Blakeslee JJ, Bandyopadhyay A, Titapiwatanakun B, Undurraga S, Khodakovskaya M, Richards EL, Krizek B, Murphy AS, Gilroy S, Gaxiola R. 2005. Arabidopsis H+-PPase AVP1 regulates auxin mediated organ development. Science 310: 121-125. PDF Suppl. data

Blakeslee JJ, Peer WA, Murphy AS (2005a) Auxin transport. Current Opinion in Plant Biology 8: 494-500. PDF

Blakeslee JJ, Peer WA, Murphy AS (2005b) MDR/PGP auxin transport proteins and endocytotic cycling. Plant Cell Monographs: Plant Endocytosis Springer, Berlin, pp. 159-176. PDF

Geisler M, Blakeslee JJ, Bouchard R, Lee OR, Vincenzetti V, Bandyopadhyay A, Titapiwantanakun B, Peer WA, Bailly A, Richards EL, Ejendal KFK, Smith AP, Baroux C, Grossniklaus U, Muller A, Hrycyna CA, Dudler R, Murphy AS, Martinoia E (2005) Cellular efflux of auxin catalyzed by the Arabidopsis MDR/PGP transporter AtPGP1. The Plant Journal 44: 179-194. PDF

Murphy AS, Bandyopadhyay A, Holstein SE, Peer WA (2005) Endocytotic cycling in PM proteins. Annual Review of Plant Biology 56:221-251. PDF

Blakeslee JJ, Peer WA, Murphy AS (2005) Auxin transport. Current Opinion in Plant Biology 8: 1-7. PDF

Peer WA, Murphy AS (2005) Flavonoids as signal molecules; Tagets of flavonoid action. In The Science of Flavonoids, E. Grotewold, sd. Springer, in press. PDF

Makam SN, Peer WA, Blakeslee JJ, Murphy AS (2005) Cultural conditions contributing to vine decline syndrome in watermelon. HortScience 40: 597-601. PDF

Baxter IR, Young JC, Armstrong G, Foster N, Bogenschutz N, Cordova T, Peer WA, Hazen SP, Murphy AS, Harper JF (2005) A plasma membrane H+-ATPase is required for the formation of proanthocyanidins in the seed coat endothelium of Arabidopsis thaliana. PNAS 102: 2649-2654. PDF

Blakeslee JJ, Bandyopadhyay A, Peer WA, Makam SN, Murphy AS (2004) PIN1 auxin efflux facilitator plays a role in phototropism. Plant Physiology 134: 28-31. PDF

Peer WA, Bandyopadhyay A, Blakeslee JJ, Srinivas MN, Chen RJ, Masson PH, Murphy AS (2004) Variation in PIN gene expression and protein localization in flavonoid mutants with altered auxin transport. Plant Cell. PDF Supplementary Figure

Muday GK, Peer WA, Murphy AS (2003) Vesicular cycling mechanisms that control auxin transport polarity. Trends Plant Sci. 8: 301-304. PDF

Smith AP, Nourizadeh S, Peer WA, Xu J, Bandyopadhyay A, Murphy AS, Goldsbrough PB (2003) Arabidopsis AtGSTF2 is regulated by ethylene and auxin, and encodes a glutathione S-transferase that interacts with flavonoids. Plant Journal 36: 433-442. PDF

Noh B, Bandyopadhyay A, Peer WA, Spalding EP, Murphy AS (2003) Enhanced gravi- and phototropism in plant mdr mutants mislocalizing the auxin efflux protein PIN1. Nature 423: 999-1002. PDF

Peer WA, Mamoudian M, Lahner B, Reeves RD, Murphy AS, Salt DE (2003) Identifying model metal hyperaccumlating plants: germplasm analysis of 20 Brassicaceae accessions from a wide geographic area. New Phytologist 159: 421-430. PDF

Peer WA, Murphy AS (2003) Floral scent of Arabidopsis lyrata (Brassicaceae). Biochemical Systematics and Ecology 31: 1193-1195. PDF

Murphy AS, Hoogner K, Peer WA, Taiz L (2002) Identification, purification, and molecular cloning of N-1-naphthylphthalmic acid -binding plasma membrane-associated aminopeptidases from Arabidopsis. Plant Physiology 128: 935-950. PDF

Brown DE, Rashotte A, Murphy AS, Normanly J, Tague BW, Peer WA, Taiz L, Muday GK (2001) Flavonoids Act as Negative Regulators of Auxin Transport in Vivo in Arabidopsis. Plant Physiol 126: 524-535. PDF

Peer WA, Brown DE, Tague BW, Muday GK, Taiz L, Murphy AS (2001) Flavonoid Accumulation Patterns of Transparent Testa Mutants of Arabidopsis. Plant Physiol 126: 536-548. PDF

Murphy AS, Peer WA, Taiz L (2000) Regulation of Auxin Transport by Aminopeptidases and Endogenous Flavonoids. Planta 211: 315-324. PDF