Alan E. Senior, Ph.D.

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Multi drug resistance in cancer; ATP synthesis in bacteria and mitochondria.

(1) Multidrug resistance in cancer. Cancer chemotherapy often fails because the tumor develops resistance to multiple drugs simultaneously. The culprit is multidrug-resistance protein (mdr) also known as P-glycoprotein. It is located in plasma membranes, and uses ATP to transport drugs out of cells. We have generated a cell line which greatly overexpresses mdr, from which enriched plasma membranes and purified protein are readily obtained. The long-term goal is to learn ways to disable or circumvent mdr protein in cancer cells.

(2) ATP synthesis and hydrolysis in F1Fo-ATP synthase. ATP synthase is the smallest known rotary motor. It uses subunit rotation to drive ATP synthesis, and ATP hydrolysis to drive subunit rotation. The subunit rotation is linked in turn to utilization or generation of a membrane proton gradient. We are using a variety of probes to study the mechanism of catalysis and to elucidate the molecular linkage between catalysis and subunit rotation. We use the E. coli enzyme and a range of molecular genetics, biochemical and biophysical techniques. In recent work we have focussed on application of fluoroscent probes of cataytic sites which have yielded rapid and sensitive information about mechanism.

Current Appointments

• Professor Emeritus - Department of Biochemistry and Biophysics (SMD)

Education
PhD Pharmacology	UK-Med Sch U Newcastle-On-Tyne	1967
BS Physiology	UK-Med Sch U Newcastle-On-Tyne	1964

Recent Journal Articles
Showing the 5 most recent journal articles. (195 available)
Li W; Brudecki LE; Senior AE; Ahmad Z. "Role of {alpha}-subunit VISIT-DG sequence residues Ser-347 and Gly-351 in the catalytic sites of Escherichia coli ATP synthase." The Journal of biological chemistry. 2009; 284(16):10747-54. Epub 2009 Feb 23.
Lee JY; Urbatsch IL; Senior AE; Wilkens S. "Nucleotide-induced structural changes in P-glycoprotein observed by electron microscopy." The Journal of biological chemistry. 2008; 283(9):5769-79. Epub 2007 Dec 19.
Carrier I; Urbatsch IL; Senior AE; Gros P. "Mutational analysis of conserved aromatic residues in the A-loop of the ABC transporter ABCB1A (mouse Mdr3)." FEBS letters. 2007; 581(2):301-8. Epub 2007 Jan 03.
Senior AE. "ATP synthase: motoring to the finish line." Cell. 2007; 130(2):220-1.
Tombline G; Urbatsch IL; Virk N; Muharemagic A; White LB; Senior AE. "Expression, purification, and characterization of cysteine-free mouse P-glycoprotein." Archives of biochemistry and biophysics. 2006; 445(1):124-8. Epub 2005 Nov 28.