Inhibition of MAPK Hog1 Results in Increased Hsp104 Aggregate Formation Probably through Elevated Arsenite Influx into the Cells, an Approach with Numerous Potential Applications

Abstract

Arsenic is a highly toxic and carcinogenic metalloid widely dispersed in the environment, contaminating water and soil and accumulating in crops. Paradoxically, arsenic is also part of modern therapy and employed in treating numerous ailments and diseases. Hence, inventing strategies to tune cellular arsenic uptake based on purpose is striking. Here, we describe an approach in which the arsenite uptake can be increased using a MAPK inhibitor. Employing microfluidic flow chambers in combination with optical tweezers and fluorescent microscopy, we elevated the influx of arsenite into the yeast Saccharomyces cerevisiae cells following short-term treatment with a Hog1 kinase inhibitor. The increase in arsenite uptake was followed on arsenite triggered redistribution of a reporter protein, Hsp104-GFP, which was imaged over time. The effect was even more pronounced when the yeast mother and daughter cells were analyzed disjointedly, an opportunity provided owing to single-cell analysis. Our data firstly provide a strategy to increase arsenite uptake and secondly show that arsenite triggered aggregates, previously shown to be sites of damaged proteins, are distributed asymmetrically and less accumulated in daughter cells. Inventing approaches to tune arsenite uptake has a great value for its use in environmental as well as medical applications.

Share and Cite:

Ahmadpour, D. , Banaeiyan, A. , Grøtli, M. , Adiels, M. , Goksör, M. and Adiels, C. (2014) Inhibition of MAPK Hog1 Results in Increased Hsp104 Aggregate Formation Probably through Elevated Arsenite Influx into the Cells, an Approach with Numerous Potential Applications. American Journal of Molecular Biology, 4, 59-91. doi: 10.4236/ajmb.2014.42008.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] Bhattacharjee, H., Rosen, B.P. and Mukhopadhyay, R. (2009) Aquaglyceroporins and Metalloid Transport: Implications in Human Diseases. Handbook of Experimental Pharmacology, 190, 309-325.
[2] Evens, A.M., Tallman, M.S. and Gartenhaus, R.B. (2004) The Potential of Arsenic Trioxide in the Treatment of Malignant Disease: Past, Present, and Future. Leukemia Research, 28, 891-900.
http://dx.doi.org/10.1016/j.leukres.2004.01.011
[3] Bagchi, S. (2007) Arsenic Threat Reaching Global Dimensions. CMAJ, 177, 1344-1345.
http://dx.doi.org/10.1503/cmaj.071456
[4] Liu, S.X., Athar, M., Lippai, I., Waldren, C. and Hei, T.K. (2001) Induction of Oxyradicals by Arsenic: Implication for Mechanism of Genotoxicity. Proceedings of the National Academy of Sciences of the United States of America, 98, 1643-1648. http://dx.doi.org/10.1073/pnas.98.4.1643
[5] Waxman, S. and Anderson, K.C. (2001) History of the Development of Arsenic Derivatives in Cancer Therapy. The Oncologist, 6, 3-10. http://dx.doi.org/10.1634/theoncologist.6-suppl_2-3
[6] Azizur Rahman, M., Hasegawa, H., Mahfuzur Rahman, M., Mazid Miah, M.A. and Tasmin, A. (2008) Arsenic Accumulation in Rice (Oryza sativa L.): Human Exposure through Food Chain. Ecotoxicology and Environmental Safety, 69, 317-324. http://dx.doi.org/10.1016/j.ecoenv.2007.01.005
[7] Tseng, C.H., Tai, T.Y., Chong, C.K., Tseng, C.P., Lai, M. S., Lin, B.J., Chiou, H.Y., Hsueh, Y.M., Hsu, K.H. and Chen, C.J. (2000) Long-Term Arsenic Exposure and Incidence of Non-Insulin-Dependent Diabetes Mellitus: A Cohort Study in Arseniasis-Hyperendemic Villages in Taiwan. Environmental Health Perspectives, 108, 847-851.
http://dx.doi.org/10.1289/ehp.00108847
[8] Meliker, J.R., Wahl, R.L., Cameron, L.L. and Nriagu, J.O. (2007) Arsenic in Drinking Water and Cerebrovascular Disease, Diabetes Mellitus, and Kidney Disease in Michigan: A Standardized Mortality Ratio Analysis. Environmental Health, 6, 4. http://dx.doi.org/10.1186/1476-069X-6-4
[9] Tamas, M.J. and Wysocki, R. (2001) Mechanisms Involved in Metalloid Transport and Tolerance Acquisition. Current Genetics, 40, 2-12. http://dx.doi.org/10.1007/s002940100234
[10] Raju, G.P. (2011) Arsenic: A Potentially Useful Poison for Hedgehog-Driven Cancers. Journal of Clinical Investigation, 121, 14-16. http://dx.doi.org/10.1172/JCI45692
[11] Nok, A.J. (2003) Arsenicals (Melarsoprol), Pentamidine and Suramin in the Treatment of Human African Trypanosomiasis. Parasitology Research, 90, 71-79.
[12] Barrett, M.P., Burchmore, R.J., Stich, A., Lazzari, J.O., Frasch, A.C., Cazzulo, J.J. and Krishna, S. (2003) The Trypanosomiases. The Lancet, 362, 1469-1480. http://dx.doi.org/10.1016/S0140-6736(03)14694-6
[13] Baker, N., De Koning, H.P., Maser, P. and Horn, D. (2013) Drug Resistance in African Trypanosomiasis: The Melarsoprol and Pentamidine Story. Trends in Parasitology, 29, 110-118. http://dx.doi.org/10.1016/j.pt.2012.12.005
[14] Barrett, J. (2003) Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukemia. Seminars in Hematology, 40, 59-71. http://dx.doi.org/10.1016/S0037-1963(03)70043-2
[15] Douer, D., Hu, W., Giralt, S., Lill, M. and Dipersio, J. (2003) Arsenic Trioxide (Trisenox®) Therapy for Acute Promyelocytic Leukemia in the Setting of Hematopoietic Stem Cell Transplantation. The Oncologist, 8, 132-140.
http://dx.doi.org/10.1634/theoncologist.8-2-132
[16] Pettersson, H.M., Pietras, A., Munksgaard Persson, M., Karlsson, J., Johansson, L., Shoshan, M.C. and Pahlman, S. (2009) Arsenic Trioxide Is Highly Cytotoxic to Small Cell Lung Carcinoma Cells. Molecular Cancer Therapeutics, 8, 160-170. http://dx.doi.org/10.1158/1535-7163.MCT-08-0595
[17] Beauchamp, E.M., Ringer, L., Bulut, G., Sajwan, K.P., Hall, M.D., Lee, Y. C., Peaceman, D., Ozdemirli, M., Rodriguez, O., Macdonald, T.J., Albanese, C., Toretsky, J.A. and Uren, A. (2011) Arsenic Trioxide Inhibits Human Cancer Cell Growth and Tumor Development in Mice by Blocking Hedgehog/GLI Pathway. Journal of Clinical Investigation, 121, 148-160. http://dx.doi.org/10.1172/JCI42874
[18] Ralph, S.J. (2008) Arsenic-Based Antineoplastic Drugs and Their Mechanisms of Action. Metal-Based Drugs, 2008, Article ID: 260146. http://dx.doi.org/10.1155/2008/260146
[19] Wysocki, R., Chery, C.C., Wawrzycka, D., Van Hulle, M., Cornelis, R., Thevelein, J.M. and Tamas, M.J. (2001) The Glycerol Channel Fps1p Mediates the Uptake of Arsenite and Antimonite in Saccharomyces cerevisiae. Molecular Microbiology, 40, 1391-1401. http://dx.doi.org/10.1046/j.1365-2958.2001.02485.x
[20] Ma, J.F., Yamaji, N., Mitani, N., Xu, X.Y., Su, Y.H., Mcgrath, S.P. and Zhao, F.J. (2008) Transporters of Arsenite in Rice and Their Role in Arsenic Accumulation in Rice Grain. Proceedings of the National Academy of Sciences of the United States of America, 105, 9931-9935. http://dx.doi.org/10.1073/pnas.0802361105
[21] Liu, Z., Shen, J., Carbrey, J.M., Mukhopadhyay, R., Agre, P. and Rosen, B.P. (2002) Arsenite Transport by Mammalian Aquaglyceroporins AQP7 and AQP9. Proceedings of the National Academy of Sciences of the United States of America, 99, 6053-6058. http://dx.doi.org/10.1073/pnas.092131899
[22] Bhattacharjee, H., Carbrey, J., Rosen, B.P. and Mukhopadhyay, R. (2004) Drug Uptake and Pharmacological Modulation of Drug Sensitivity in Leukemia by AQP9. Biochemical and Biophysical Research Communications, 322, 836-841.
http://dx.doi.org/10.1016/j.bbrc.2004.08.002
[23] Thorsen, M., Di, Y., Tangemo, C., Morillas, M., Ahmadpour, D., Van Der Does, C., Wagner, A., Johansson, E., Boman, J., Posas, F., Wysocki, R., Tamas, M.J. and Boone, C. (2006) The MAPK Hog1p Modulates Fps1p-Dependent Arsenite Uptake and Tolerance in Yeast. Molecular Biology of the Cell, 17, 4400-4410.
http://dx.doi.org/10.1091/mbc.E06-04-0315
[24] Hohmann, S. (2009) Control of High Osmolarity Signalling in the Yeast Saccharomyces cerevisiae. FEBS Letters, 583, 4025-4029. http://dx.doi.org/10.1016/j.febslet.2009.10.069
[25] Hohmann, S., Krantz, M. and Nordlander, B. (2007) Yeast Osmoregulation. Methods in Enzymology, 428, 29-45.
http://dx.doi.org/10.1016/S0076-6879(07)28002-4
[26] Brewster, J.L., De Valoir, T., Dwyer, N.D., Winter, E. and Gustin, M.C. (1993) An Osmosensing Signal Transduction Pathway in Yeast. Science, 259, 1760-1763. http://dx.doi.org/10.1126/science.7681220
[27] Hohmann, S. (2002) Osmotic Stress Signaling and Osmoadaptation in Yeasts. Microbiology and Molecular Biology Reviews, 66, 300-372. http://dx.doi.org/10.1128/MMBR.66.2.300-372.2002
[28] Westfall, P.J. and Thorner, J. (2006) Analysis of Mitogen-Activated Protein Kinase Signaling Specificity in Response to Hyperosmotic Stress: Use of an Analog-Sensitive HOG1 Allele. Eukaryotic Cell, 5, 1215-1228.
http://dx.doi.org/10.1128/EC.00037-06
[29] Diner, P., Veide Vilg, J., Kjellen, J., Migdal, I., Andersson, T., Gebbia, M., Giaever, G., Nislow, C., Hohmann, S., Wysocki, R., Tamas, M.J. and Grotli, M. (2011) Design, Synthesis and Characterization of a Highly Effective Hog1 Inhibitor: A Powerful Tool for Analyzing MAP Kinase Signaling in Yeast. PLoS ONE, 6, Article ID: e20012.
http://dx.doi.org/10.1371/journal.pone.0020012
[30] Wurgler-Murphy, S.M., Maeda, T., Witten, E.A. and Saito, H. (1997) Regulation of the Saccharomyces cerevisiae HOG1 Mitogen-Activated Protein Kinase by the PTP2 and PTP3 Protein Tyrosine Phosphatases. Molecular and Cellular Biology, 17, 1289-1297.
[31] Hamngren, C., Dinér, P., Grøtli, M., Goksör, M. and Adiels, B. (2012) Design and Evaluation of a Microfluidic System for Inhibition Studies of Yeast Cell Signaling. Proceedings of SPIE, 8458, 84582K-1.
http://dx.doi.org/10.1117/12.929728
[32] Sanchez, Y., Taulien, J., Borkovich, K.A. and Lindquist, S. (1992) Hsp104 Is Required for Tolerance to Many Forms of Stress. EMBO Journal, 11, 2357-2364.
[33] Jacobson, T., Navarrete, C., Sharma, S.K., Sideri, T.C., Ibstedt, S., Priya, S., Grant, C.M., Christen, P., Goloubinoff, P. and Tamas, M.J. (2012) Arsenite Interferes with Protein Folding and Triggers Formation of Protein Aggregates in Yeast. Journal of Cell Science, 125, 5073-5083. http://dx.doi.org/10.1242/jcs.107029
[34] Kawai, R., Fujita, K., Iwahashi, H. and Komatsu, Y. (1999) Direct Evidence for the Intracellular Localization of Hsp104 in Saccharomyces cerevisiae by Immunoelectron Microscopy. Cell Stress & Chaperones, 4, 46-53.
[35] Lum, R., Tkach, J.M., Vierling, E. and Glover, J.R. (2004) Evidence for an Unfolding/Threading Mechanism for Protein Disaggregation by Saccharomyces cerevisiae Hsp104. Journal of Biological Chemistry, 279, 29139-29146.
http://dx.doi.org/10.1074/jbc.M403777200
[36] Eriksson, E., Enger, J., Nordlander, B., Erjavec, N., Ramser, K., Goksor, M., Hohmann, S., Nystrom, T. and Hanstorp, D. (2007) A Microfluidic System in Combination with Optical Tweezers for Analyzing Rapid and Reversible Cytological Alterations in Single Cells upon Environmental Changes. Lab on a Chip, 7, 71-76.
http://dx.doi.org/10.1039/b613650h
[37] Sott, K., Eriksson, E., Petelenz, E. and Goksor, M. (2008) Optical Systems for Single Cell Analyses. Expert Opinion on Drug Discovery, 3, 1323-1344. http://dx.doi.org/10.1517/17460441.3.11.1323
[38] Schaber, J., Adrover, M.A., Eriksson, E., Pelet, S., Petelenz-Kurdziel, E., Klein, D., Posas, F., Goksor, M., Peter, M., Hohmann, S. and Klipp, E. (2010) Biophysical Properties of Saccharomyces cerevisiae and Their Relationship with HOG Pathway Activation. European Biophysics Journal, 39, 1547-1556. http://dx.doi.org/10.1007/s00249-010-0612-0
[39] Eriksson, E., Sott, K., Lundqvist, F., Sveningsson, M., Scrimgeour, J., Hanstorp, D., Goksor, M. and Graneli, A. (2010) A Microfluidic Device for Reversible Environmental Changes around Single Cells Using Optical Tweezers for Cell Selection and Positioning. Lab on a Chip, 10, 617-625. http://dx.doi.org/10.1039/b913587a
[40] Petelenz-Kurdziel, E., Eriksson, E., Smedh, M., Beck, C., Hohmann, S. and Goksor, M. (2011) Quantification of Cell Volume Changes upon Hyperosmotic Stress in Saccharomyces cerevisiae. Integrative Biology, 3, 1120-1126.
http://dx.doi.org/10.1039/c1ib00027f
[41] Gustavsson, A.K., Van Niekerk, D.D., Adiels, C.B., Du Preez, F.B., Goksor, M. and Snoep, J.L. (2012) Sustained Glycolytic Oscillations in Individual Isolated Yeast Cells. FEBS Journal, 279, 2837-2847.
http://dx.doi.org/10.1111/j.1742-4658.2012.08639.x
[42] Babazadeh, R., Adiels, C.B., Smedh, M., Petelenz-Kurdziel, E., Goksor, M. and Hohmann, S. (2013) Osmostress-Induced Cell Volume Loss Delays Yeast Hog1 Signaling by Limiting Diffusion Processes and by Hog1-Specific Effects. PLoS ONE, 8, Article ID: e80901. http://dx.doi.org/10.1371/journal.pone.0080901
[43] Beck, C. and Goksör, M. (2012) Microfluidics in Single Cell Analysis. In: Kelly, R.T., Ed., Advances in Microfluidics, InTech, Morn Hill, 173-192.
[44] Neuman, K.C., Chadd, E.H., Liou, G.F., Bergman, K. and Block, S.M. (1999) Characterization of Photodamage to Escherichia coli in Optical Traps. Biophysical Journal, 77, 2856-2863.
http://dx.doi.org/10.1016/S0006-3495(99)77117-1
[45] Liang, H., Vu, K.T., Krishnan, P., Trang, T.C., Shin, D., Kimel, S. and Berns, M.W. (1996) Wavelength Dependence of Cell Cloning Efficiency after Optical Trapping. Biophysical Journal, 70, 1529-1533.
http://dx.doi.org/10.1016/S0006-3495(96)79716-3
[46] Smedh, M., Beck, C.A., Sott, K. and Goksör, M. (2010) CellStress—Open Source Image Analysis Program for Single— Cell Analysis. Proceedings of SPIE, 7762, 77622N-1. http://dx.doi.org/10.1117/12.860403
[47] Fujita, K., Kawai, R., Iwahashi, H. and Komatsu, Y. (1998) Hsp104 Responds to Heat and Oxidative Stress with Different Intracellular Localization in Saccharomyces cerevisiae. Biochemical and Biophysical Research Communications, 248, 542-547. http://dx.doi.org/10.1006/bbrc.1998.9008
[48] Bain, J., Plater, L., Elliott, M., Shpiro, N., Hastie, C.J., Mclauchlan, H., Klevernic, I., Arthur, J.S., Alessi, D.R. and Cohen, P. (2007) The Selectivity of Protein Kinase Inhibitors: A Further Update. Biochemical Journal, 408, 297-315.
http://dx.doi.org/10.1042/BJ20070797
[49] Torres-Quiroz, F., Garcia-Marques, S., Coria, R., Randez-Gil, F. and Prieto, J.A. (2010) The Activity of Yeast Hog1 MAPK Is Required during Endoplasmic Reticulum Stress Induced by Tunicamycin Exposure. Journal of Biological Chemistry, 285, 20088-20096. http://dx.doi.org/10.1074/jbc.M109.063578
[50] Mishra, S., Jha, A.B. and Dubey, R.S. (2011) Arsenite Treatment Induces Oxidative Stress, Upregulates Antioxidant System and Causes Phytochelatin Synthesis in Rice Seedlings. Protoplasma, 248, 565-577.
http://dx.doi.org/10.1007/s00709-010-0210-0
[51] Tamas, M.J., Luyten, K., Sutherland, F.C., Hernandez, A., Albertyn, J., Valadi, H., Li, H., Prior, B.A., Kilian, S.G., Ramos, J., Gustafsson, L., Thevelein, J.M. and Hohmann, S. (1999) Fps1p Controls the Accumulation and Release of the Compatible Solute Glycerol in Yeast Osmoregulation. Molecular Microbiology, 31, 1087-1104.
http://dx.doi.org/10.1046/j.1365-2958.1999.01248.x
[52] Wysocki, R., Bobrowicz, P. and Ulaszewski, S. (1997) The Saccharomyces cerevisiae ACR3 Gene Encodes a Putative Membrane Protein Involved in Arsenite Transport. Journal of Biological Chemistry, 272, 30061-30066.
http://dx.doi.org/10.1074/jbc.272.48.30061
[53] Ghosh, M., Shen, J. and Rosen, B.P. (1999) Pathways of As(III) Detoxification in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America, 96, 5001-5006.
http://dx.doi.org/10.1073/pnas.96.9.5001
[54] Swain, P.S., Elowitz, M.B. and Siggia, E.D. (2002) Intrinsic and Extrinsic Contributions to Stochasticity in Gene Expression. Proceedings of the National Academy of Sciences of the United States of America, 99, 12795-12800.
http://dx.doi.org/10.1073/pnas.162041399
[55] Johnston, I.G., Gaal, B., Neves, R.P., Enver, T., Iborra, F.J. and Jones, N.S. (2012) Mitochondrial Variability as a Source of Extrinsic Cellular Noise. PLoS Computational Biology, 8, Article ID: e1002416.
http://dx.doi.org/10.1371/journal.pcbi.1002416
[56] Cookson, N.A., Cookson, S.W., Tsimring, L.S. and Hasty, J. (2010) Cell Cycle-Dependent Variations in Protein Concentration. Nucleic Acids Research, 38, 2676-2681. http://dx.doi.org/10.1093/nar/gkp1069
[57] Aguilaniu, H., Gustafsson, L., Rigoulet, M. and Nystrom, T. (2003) Asymmetric Inheritance of Oxidatively Damaged Proteins during Cytokinesis. Science, 299, 1751-1753. http://dx.doi.org/10.1126/science.1080418
[58] Huq, S.M., Joardar, J.C., Parvin, S., Correll, R. and Naidu, R. (2006) Arsenic Contamination in Food-Chain: Transfer of Arsenic into Food Materials through Groundwater Irrigation. Journal of Health, Population, and Nutrition, 24, 305-316.
[59] Salerno, M. and Garnier-Suillerot, A. (2003) Resistance to Arsenic- and Antimony-Based Drugs. Bioinorganic Chemistry and Applications, 1,189-198. http://dx.doi.org/10.1155/S1565363303000153
[60] Isayenkov, S.V. and Maathuis, F.J. (2008) The Arabidopsis thaliana Aquaglyceroporin AtNIP7;1 Is a Pathway for Arsenite Uptake. FEBS Letters, 582, 1625-1628. http://dx.doi.org/10.1016/j.febslet.2008.04.022

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.