User:Rockstarmabel/sandbox
Mabel Hokin | |
|---|---|
| Born | February 9, 1924 |
| Died | August 17, 2003 (aged 79) |
| Nationality | English |
| Known for | Discovery of Phosphoinositide Effect |
| Spouse(s) | Lowell Hokin, Bernard Biales |
| Awards | Hilldale Award (1994) |
| Scientific career | |
| Fields | Biochemistry |
Mabel Ruth Hokin (née Neaverson) (9 February 1924 – 17 August 2003) was an English biochemist and research scientist who focused her work primarily on cell signaling. In the 1950s, she met and married fellow biochemist Lowell Hokin [1]. Jointly, they prospered three children. Initially, they researched together at the University of Sheffield in England[1]. Later, they moved to Montreal, Quebec to work at McGill University[1]. Finally, they settled in Madison, Wisconsin to conduct their research at the University of Wisconsin[2]. They completed many experiments related to cell signaling that led to the accidental but crucial discovery of the Phosphoinositide (PI) Effect[1]. Their work, which laid the foundation for the discovery of IP3 and DAG as secondary messengers, won them the University of Wisconsin Hilldale Award in 1994[1]. Mabel Hokin died in Madison, Wisconsin on August 17, 2003 at the age of 79[2].
Early Life[edit]
Mabel Ruth Hokin (née Neaverson) was raised in Sheffield, England[2]. During her youth, she received a national prize for Bible knowledge. At the age of 15, she assisted Eastern European refuges in the Second World War. Her passion for the war effort led her to serve in the British Land Army[2]. In this position, she took on many roles including working as a steel technician, supervising mentally ill agricultural workers, and assisting the nurses[1]. After the war ended, she began her scientific career.
Academic Career[edit]
Mabel first worked as a technician in Sir Hans Krebs' laboratory at the University of Sheffield. At his insistence, she began studies at the university and received a Bachelor of Physiology and Biochemistry in 1949 [1]. Three years later, Mabel completed her PhD in Biochemistry under Dr. Quentin H. Gibson. She began her research at the University of Sheffield. After marrying her co-worker Lowell Hokin, she moved to Montreal in 1952 where she completed her postdoctoral fellowship under Dr. J.H. Quastel at McGill University[1]. Subsequent to her fellowship, Mabel continued her work at McGill in the Montreal General Hospital Research Institute in collaboration with Lowell. Together, they made the fortunate but unintended discovery of the PI Effect while studying RNA. Their findings revealed the importance of lipids to cell signaling[3]. Mabel relocated to the Department of Physiological Chemistry at the University of Wisconsin with Lowell in 1957 to work as a research associate. In 1994, the Hokins received the Hilldale Award from the University of Wisconsin for their research in the field of phospholipid signalling.
Research into the PI Effect[edit]
The discovery of the PI Effect began at the University of Sheffield. Along with her future husband Lowell, Mabel was researching the incorporation of 32P into RNA as a result of acetylcholine stimulation of pancreatic slices. They were interested in understanding the mechanism of RNA synthesis and its involvement in protein production[4]. Due to their relocation to McGill, purification of their RNA samples was delayed. However, when they isolated the RNA fraction, the source of radioactivity was no longer present. Further investigation revealed that the 32P was localized in the phospholipid fraction of the pancreatic thin slices of fasted pigeons. Up until this point, phospholipids had been considered to be metabolically inactive[2]. Little was known at the time about the intracellular effects of the hormones and neurotransmitters that bind cell-surface receptors, and the Hokins’ result was a fortuitous one for the field of cell signaling.
This observation was first presented in 1953 [3]. Acetylcholine and carbamylcholine stimulation increased pancreatic enzyme secretion and phospholipid turnover 5 to 9 fold after 2 hour incubations [3]. The central assay used to determine phospholipid changes was the magnitude of 32P radioactivity in the sample detected by a Geiger counter. Following the observation of acetylcholine-induced phospholipid turnover, the focus turned to identifying this effect in exocrine and endocrine tissues other than the pancreas. From 1955 to 1958, a series of papers were published revealing the presence of phospholipid turnover in the cerebral cortex[5][6], the adrenal medulla[7], and the adrenal cortex[8]. In her and Lowell’s words, “[our] present work indicates that phosphoinositides are involved in the secretion of protein from the inside of the pancreatic acinar cell into the lumen . . . It is tempting to think that the active transport out of the cell of many other types of molecules may involve phosphoinositides”[9].
With the confirmation that phospholipid turnover was widespread, analysis techniques such as two-dimensional chromatography and new deacylation reactions were devised to isolate which particular phospholipids were involved in enzyme secretion [4]. Phosphatidic acid and phosphatidylinositol were found to be the compounds accumulating 32P[10]. The PI effect was coined in the Hokins' 1958 paper in Biochimica et Biophysica Acta[4]. With this knowledge, the drive to identify the molecular intricacies of the PI Effect began, and a series of papers were published by the Hokins through the early 1960s. It had been observed that acetylcholine induced the secretion of salt in the supraorbital gland of albatrosses and sea gulls. This attracted the Hokins’ attention to use the birds as models to elucidate the PI Effect. It was found that acetylcholine stimulation accompanied the turnover of phospholipids, especially phosphatidic acid and phosphatidylinositol[11]. A phosphorylation/dephosphorylation cycle was proposed as the underlying mechanism of the PI Effect at a symposium in 1964[12]. According to this framework, acetylcholine stimulation prompted phospholipase C (PLC) to convert phosphatidylinositol to diglyceride and inositol 1-monophospate, which through ATP hydrolysis produced phosphatidic acid[4]. This pathway accounted for the heightened concentration of phosphatidic acid observed in the endomembrane system, and was believed to mediate salt secretion. Removal of the stimulus caused phosphatidic acid to be dephosphorylated to phosphatidylinositol according to this hypothesis, and this was observed through the addition of the cholinergic antagonist atropine[4].
Their proposal ultimately proved to be incomplete, but their inclusion of PLC and phosphatidylinositol in their cycle was evidence of the progress they had made in understanding the intricacies of the PI Effect. In fact, back in the early 1960s, the Hokins had published papers that had mentioned a decrease in the concentration of polyphosphoinositides such as phosphatidylinositol 4,5-bisphosphate (PIP2) in response to acetylcholine[4]. Unfortunately, the Hokins did not continue to investigate these observations. They were not returned to and expanded upon until Michell published a comprehensive review on the PI Effect in 1975. He proposed that the Hokins had discovered a signalling pathway of comparable importance to Rall, Sutherland, and Berthet’s cAMP system[13]. At this point, other researchers began to link a coincidental intracellular calcium increase with the PI effect. It was unknown whether it was the cause of the response or if it was an effect. Michell’s review provided a coherent hypothesis building upon the Hokins’ research. According to his model, PLC hydrolyzed phosphatidylinositols to affect intracellular calcium levels, ion channel conductance, and other cellular processes such as vesicle release[12]. Eventually, the rest of the pathway was deduced by researchers such as Michael Berridge and Yasutomi Nishizuka [14]. In the early 1980s, PIP2 was identified as the phospholipid being hydrolyzed. The products inositol 1,4,5-triphosphate (IP3) and diacyl glycerol (DAG) were found to mediate the release of calcium and the activation of Protein Kinase C (PKC) respectively [14]. By the mid 1980s, thirty years after the Hokins’ initial paper, the intracellular mechanisms of the PI Effect had been finally elucidated and its exceptional relevance to cell signalling gained widespread approval. The Hokins may not have fully interpreted their results, but their initial contributions formed the foundation for other researchers to unravel the ubiquitous IP3/DAG pathway.
Later Life[edit]
Mabel and Lowell divorced after moving to Wisconsin but remained colleagues. They had three children together: Catherine, Linda, and Samuel[1]. Mabel later married Bernard Biales and published under the name Hokin-Neaverson from 1970 until she retired [2]. Through the 1970s, she continued working on the PI Effect, but with her divorce from Lowell and her establishment in the Department of Psychiatry in 1968 at the University of Wisconsin, she gradually turned her attention to neurotransmitters and the biological causes of mental illness[1]. Her distaste for psychodynamic theories led her to propose a biochemical basis for bipolar disorder[1]. In two papers published in 1989 in Neuropychobiology, she proposed that there was a decrease in Na/K-ATPase activity in patients suffering from the disease[15]. Lithium, a clinically effective treatment for the disorder, was found by to reverse the pump’s activity to normal levels [16]. While Mabel Hokin will primarily be remembered for her contribution to the field of phospholipid signalling, she concluded her long career in science by exploring an entirely different avenue of research. She also served as a professor of biological psychiatry and biomolecular chemistry and established a scholarship in memory of her late daughter, Catherine [1]. Mabel retired in 1995 to become a Professor Emerita and passed away in 2003.
References[edit]
- ^ a b c d e f g h i j k l [1], Klein, M., Kalin, N., & Kelley, A. (2004, February 2). Memorial Resolution of the Faculty of the University of Wisconsin – Madison on the Death of Professor Emerita Mabel R. Hokin – Neaverson.
- ^ a b c d e f [2], Michell, B. (2003) Obituary: Mabel R. Hokin (1924–2003). The Biochemist. December
- ^ a b c [3], Hokin, M. R. & Hokin, L. E. (1953). Enzyme secretion and the incorporation of 32P into phospholipides of pancreas slices. J.Biol.Chem., 203, 967-977.
- ^ a b c d e f [4], Hokin, L.E. & Hokin-Neaverson, M. (1989) Commentary by Lowell E. Hokin and Mabel Hokin-Neaverson on ‘Effects of acetylcholine on the turnover of phosphoryl units in individual phospholipids of pancreas slices and brain cortex slices’. Biochim. Biophys. Acta., 1000, 465-469.
- ^ [5], Hokin, L. E. & Hokin, M. R. (1955). Effects of acetylcholine on phosphate turnover in phospholipides of brain cortex in vitro. Biochim.Biophys.Acta, 16, 229-237.
- ^ [6], Hokin, L. E. & Hokin, M. R. (1958). Acetylcholine and the exchange of inositol and phosphate in brain phosphoinositide. J.Biol.Chem., 233, 818-821.
- ^ [7], Hokin, M. R., Benfrey, B. G., & Hokin, L. E. (1958). Phospholipides and adrenaline secretion in guinea pig adrenal medulla. J.Biol.Chem., 233, 814-817.
- ^ [8], Hokin, M. R., Hokin, L. E., Saffran, M., Schally, A. V., & Zimmermann, B. U. (1958). Phospholipides and the secretion of adrenocorticotropin and of corticosteroids. J.Biol.Chem., 233, 811-813.
- ^ [9], Hokin, L. E. & Hokin, M. R. (1958). Phosphoinositides and protein secretion in pancreas slices. J.Biol.Chem., 233, 805-810.
- ^ [10], Hokin, L. E. & Hokin, M. R. (1965). The chemistry of cell membranes. Sci.Am., 213, 78-86.
- ^ [11], Hokin, L. E. & Hokin, M. R. (1960). Studies on the carrier function of phosphatidic acid in sodium transport. I. The turnover of phosphatidic acid and phosphoinositide in the avian salt gland on stimulation of secretion. J.Gen.Physiol, 44, 61-85.
- ^ a b Ord, M.G. , & Stocken, L.A. (1997). Foundations of Modern Biochemistry: Further Milestones in Biochemistry (Vol. 3). Elsevier Science.
- ^ [12], Rall, T. W., Sutherland, E. W. Berthet, J. (1957). The relationship of epinephrine and glucagon to liver phosphorylase. IV. Effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. J.Biol.Chem., 224, 463-475.
- ^ a b [13], Irvine, R.F. (2003). 20 years of Ins(1,4,5)P3,and 40 years before. Nat. Rev. Mol. Cell. Biol., 4, 586-90.
- ^ [14], Hokin-Neaverson, M. & Jefferson, J. W. (1989). Erythrocyte sodium pump activity in bipolar affective disorder and other psychiatric disorders. Neuropsychobiology, 22, 1-7.
- ^ [15], Hokin-Neaverson, M. & Jefferson, J. W. (1989). Deficient erythrocyte NaK-ATPase activity in different affective states in bipolar affective disorder and normalization by lithium therapy. Neuropsychobiology, 22, 18-25.