541 Mark Jefferson Science Complex
Ypsilanti, Michigan 48197
1) Regulation of Insulin-Like Growth Factor Binding Protein-3 (IGFBP-3) and β-Amyloid by Humanin (HN)
IGFBP-3, β-Amyloid, and HN have been implicated to play a role in both Alzheimer's disease (AD) and cancer.
Role in Cancer: Extracellularly, IGFBP-3 has been reported to play a role in cancer senescence by blocking proliferation of certain cancer cells. Moreover, IGFBP3 protein levels have been shown to decrease during the progression from benign to metastatic cancer. IGFBP3 is synthesized at a lower level by some cancer cells and secreted into the extracellular environment. More recently, β-Amyloid has been shown to inhibit tumor cell proliferation. While HN has been implicated in cancer, its role is not clear.
Role in Alzheimer's disease (AD): AD is the sixth-leading cause of death in the United States, and accounts for 60-80% of all cases of dementia, an estimated number of 5.4 million Americans in 2012. Both IGFBP-3 and β-Amyloid can induce neuronal cell death seen in AD. HN is a peptide that exhibits neuroprotective and cytoprotective effects in AD, Huntington's disease, stroke, prion diseases, and diabetes. HN is known to protect against neuronal cell death induced by IGFBP-3 and β-Amyloid.
We are investigating how HN binds to both IGFBP-3 and β-amyloid in vitro and how it guards against cell death induced by IGFBP3 and β-amyloid. Techniques that include kinetics, competitive binding assays, immunoprecipitation, SDS-PAGE, western blotting, tissue culture, bioinformatics and computational modeling are used to understand the mechanism by which HN binding to IGFPB-3 and β-amyloid 1) protects against neuronal cell death and 2) affect cancer cell survival. This research will likely provide an insight in the development of new cancer, and Alzheimer's therapeutics via a mechanism likely to differ from that of currently available pharmaceuticals.
2) Pyrimidine Biosynthesis
Nucleotides play a critical role in cellular activities by serving as activated precursors of RNA and DNA, for example.
In prokaryotes, the first three enzymes in pyrimidine biosynthesis, CPS, ATC, and DHO, are commonly expressed separately and can function independently or associate into multifunctional complexes as in Aquifex aeolicus. In mammals, the enzymes are expressed as a multifunctional protein, CAD, whose activation is a prerequisite for the growth of tumors and neoplastic tissues. We are investigating the structure/function of certain intrinsically disordered regions on the DHO and their subsequent order upon noncovalent association with ATC. Six DHO and six ATC chains form a hollow dodecamer, in which the 12 active sites face an internal reaction chamber that is approximately 60 Å in diameter and connected to the cytosol by narrow tunnels. Enzyme kinetics and protein interaction methods are used to investigate the functional and physical linkages of this remarkable dodecameric protein architecture.
Current National Institutes of Health Support
Probing the Role of Insulin-Like Growth Factor-Binding Protein 3 and Humanin in Regulating Hyaluronan Function.
Previous National Institutes of Health Support
Signaling Cascades, Allostery and the Pyrimidine Pathway
The complete list of published work can be found in my bibliography.
Regulation of Soluble E-Cadherin Signaling in Non-Small-Cell Lung Cancer Cells by Nicotine, BDNF, and β-Adrenergic Receptor Ligands, Ravel Ray, Stuti Goel, Hind Al Khashali, Ban Darweesh, Ben Haddad, Caroline Wozniak, Robert Ranzenberger, Jeneen Khalil, Jeffrey Guthrie, Deborah Heyl, and Hedeel Guy Evans, Biomedicines, 11(9), 2555 (2023). https://doi.org/10.3390/biomedicines11092555
Phosphorylation of IGFBP-3 by Casein Kinase 2 Blocks Its Interaction with Hyaluronan, Enabling HA-CD44 Signaling Leading to Increased NSCLC Cell Survival and Cisplatin Resistance, Kai-ling Coleman, Michael Chiaramonti, Ben Haddad, Robert Ranzenberger, Heather Henning, Hind Al Khashali, Ravel Ray, Ban Darweesh, Jeffrey Guthrie, Deborah Heyl, and Hedeel Guy Evans, Cells 12, 405 (2023). https://doi.org/10.3390/cells12030405
Opposing Roles of IGFBP-3 and Heparanase in Regulating A549 Lung Cancer Cell Survival, Hind Al Khashali, Jadziah Wareham, Ravel Ray, Ben Haddad, Kai-Ling Coleman, Robert Ranzenberger, Patrick McCombs, Jeffrey Guthrie, Deborah Heyl and Hedeel Guy Evans, Cells, 11, 3533 (2022). https://doi.org/10.3390/cells11223533
Regulation of Cisplatin Resistance in Lung Cancer Cells by Nicotine, BDNF, and a β-Adrenergic Receptor Blocker, Ravel Ray, Hind Al Khashali, Ben Haddad, Jadziah Wareham, Kai-Ling Coleman, Danyah Alomari, Robert Ranzenberger, Jeffrey Guthrie, Deborah Heyl and Hedeel Guy Evans, Int. J. Mol. Sci., 23, 12829 (2022). https://doi.org/10.3390/ijms232112829
Regulation of the Soluble Amyloid Precursor Protein α (sAPPα) Levels by Acetylcholinesterase and Brain-Derived Neurotrophic Factor in Lung Cancer Cell Media, Hind Al Khashali, Ravel Ray, Kai-Ling Coleman, Sarah Atali, Ben Haddad, Jadziah Wareham, Jeffrey Guthrie, Deborah Heyl, Hedeel Guy Evans, Int. J. Mol. Sci.,23(18) 10746 (2022). https://doi.org/10.3390/ijms231810746
Differences in the Relative Abundance of ProBDNF and Mature BDNF in A549 and H1299 Human Lung Cancer Cell Media, Sadaf Dorandish, Sarah Atali, Ravel Ray, Hind Al Khashali, Kai-Ling Coleman, Jeffrey Guthrie, Deborah Heyl, Hedeel Guy Evans, Int. J. Mol. Sci., 22(13), 7059 (2021).https://doi.org/10.3390/ijms22137059
Regulation of Amyloid-β Levels by Matrix Metalloproteinase-2/9 (MMP2/9) in the Media of Lung Cancer Cells, Sadaf Dorandish, Asana Williams, Sarah Atali, Sophia Sendo, Deanna Price, Colton Thompson, Jeffrey Guthrie, Deborah Heyl, and Hedeel Guy Evans, Nature/Scientific Reports 11, 9708 (2021). https://doi.org/10.1038/s41598-021-88574-0
Interaction of amyloid beta with humanin and acetylcholinesterase is modulated by ATP, Sarah Atali, Sadaf Dorandish, Jonathan Devos, Asana Williams, Deanna Price, Jaylen Taylor, Jeffrey Guthrie, Deborah Heyl, and Hedeel Guy Evans* FEBS Open Bio. First published: 3 November 2020 https://doi.org/10.1002/2211-5463.13023
Biochemical determinants of the IGFBP-3-hyaluronan interaction, Sadaf Dorandish, Jonathan Devos, Bradley Clegg, Deanna Price, Robert Muterspaugh, Jeffrey Guthrie, Deborah Heyl, and Hedeel Guy Evans FEBS Open Bio. First published: 27 June 2020. https://doi.org/10.1002/2211-5463.12919
Humanin blocks aggregation of amyloid beta induced by acetylcholinesterase, an effect abolished in the presence of IGFBP-3. Deanna Price, Sadaf Dorandish, Asana Williams, Brandon Iwaniec, Alexis Stephens, Keyan Marshall, Jeffrey Guthrie, Deborah Heyl, and Hedeel Guy Evans. Biochemistry. 2020 May 8. doi:10.1021/acs.biochem.0c00274. [Epub ahead of print]
IGFBP-3 Blocks Hyaluronan-CD44 Signaling, Leading to Increased Acetylcholinesterase Levels in A549 Cell Media and Apoptosis in a p53-Dependent Manner. Deanna Price, Robert Muterspaugh, Bradley Clegg, Asana Williams, Alexis Stephens, Jeffrey Guthrie, Deborah Heyl, and Hedeel Guy Evans (2020) Scientific Reports 10:5083 https://doi.org/10.1038/s41598-020-61743-3
Using Small Peptide Segments of Amyloid-β and Humanin to Examine their Physical Interactions. Deborah L. Heyl, Brandon Iwaniec, Daniel Esckilsen, Deanna Price, Prathyusha Guttikonda, Jennifer Cooper, Julia Lombardi, Maria Milletti, and Hedeel Guy Evans (2019) Protein Pept Lett, 26 (7), 502-511.
Characterizing the Binding of Dopamine D1-D2 Receptors in Vitro and in Temporal and Frontal Lobe Tissue Total Protein. Deborah L. Heyl, Margaret Champion, Robert Muterspaugh, Megan Connolly, Adam Baraka, Pouya Khazaei, Briana Moe, Zeinab Al-Sheemary, Nael Jaber, and Hedeel Guy-Evans (2019) FEBS Letters, Article DOI: 10.1002/1873-3468.13351 https://www.ncbi.nlm.nih.gov/pubmed/30821397
Pressure-induced activation of latent Dihydroorotase from Aquifex aeolicus as revealed by high pressure protein crystallography. Thierry Prangé, Eric Girard, Roger Fourme, Anne Claire Dhaussy, Brian E.P. Edwards, Asmita Vaishnav, Chandni Patel, Hedeel Guy-Evans, Guy Hervé and David Evans (2019) The FEBS Journal (FJ-18-1006). DOI: 10.1111/febs.14758 https://www.ncbi.nlm.nih.gov/pubmed/30657257
Interaction of Insulin-Like Growth Factor-Binding protein 3 With Hyaluronan and Its Regulation by Humanin and CD44. Robert Muterspaugh, Deanna Price, Daniel Esckilsen, Sydney McEachern, Jeffrey Guthrie, Deborah Heyl, Hedeel Guy Evans, Biochemistry, 2018, 57 (39), pp 5726–5737
D-Amino Acid Analogues of the Antimicrobial Peptide CDT Exhibit Anti-Cancer Properties in A549, a Human Lung Adenocarcinoma Cell Line. Hedeel Guy Evans, Jeffrey W. Guthrie, Murali Jujjavarapu, Nathan Hendrickson, Anna Eitel, Yeji Park, Jennifer Garvey, Rebecca Newman, Daniel Esckilsen, and Deborah L. Heyl (2017) Protein Peptide Letters 24 (7), 590-598.
Activation of latent dihydroorotase from Aquifex aeolicus by pressure. Kinetic studies under pressure. Guy Hervé, Hedeel Guy Evans, Roshini Fernando, Chandni Patel, Fatme Hachem and David R. Evans (2017) JBC 292, 629–637. doi: 10.1074/jbc.M116.739862
Team-Based Learning, Faculty Research, and Grant Writing Brings Significant Learning Experiences to an Undergraduate Biochemistry Laboratory Course: Hedeel Guy Evans, Deborah L. Heyl, and Peggy Liggit (2016), Journal of Chemical Education, 93 (6), 1027–1033.
Humanin Peptide Binds to Insulin-Like Growth Factor-Binding Protein 3 (IGFBP3) and regulates its interaction with importin-β (2015) Evert Njomen, Hedeel Guy- Evans, Samanthi Herath Gedara, Deborah L. Heyl, Protein Pept Lett. 2015;22(10):869–876.
Intersubunit Communication in the Dihydroorotase-Aspartate Transcarbamoylase Complex of Aquifex aeolicus Hedeel Guy Evans, Roshini Fernando, Asmita Vaishnav, Mahalakshmi Kotichukkala, Deborah L. Heyl, Joseph S. Brunzelle, Brian F.P. Edwards, and David R. Evans (2014) Peptide Science, 23(1), 100–109.
The Mononuclear Metal Center of Type I Dihydroorotase from Aquifex aeolicus (2013) Brian F. P. Edwards, Roshini Fernando, Philip D. Martin, Edward Grimley, Melissa Cordes, Asmita Vaishnav, Joseph S. Brunzelle, Hedeel Guy Evans and David R. Evans, Manuscript accepted in BMC Biochemistry.
The Smallest Active Carbamoyl Phosphate Synthetase Was Identified in the Human Gut Archaeon Methanobrevibacter smithii (2012) Popa E, Perera N, Kibédi-Szabó CZ, Guy-Evans H, Evans DR, Purcarea C, J Mol Microbiol Biotechnol Oct 27;22(5):287–299.
FLASH knockdown sensitizes cells to Fas-mediated apoptosis via down-regulation of the anti-apoptotic proteins, MCL-1 and Cflip short. Chen S, Evans HG, Evans DR. PLoS One. 2012; 7(3):e32971. Epub Mar. 9, 2012.
Synthesis of small peptides to probe oligomeric enzyme structure in pyrimidine biosynthesis. Betsy Huang, Allesha Cutlip, Raneem AlKhatib, Mahalakshmi Kotichukkala, Hedeel Evans and Deborah L. Heyl; Proceedings of the 22nd American Peptide Symposium Michal Lebl (Editor) American Peptide Society, 2011.
FAM129B/minerva, a novel adherens junction associated protein suppresses apoptosis in hela cells. Chen S, Guy Evans H, Evans DR., J Biol Chem. 2011 Mar 25;286(12):10201–9. Epub Dec. 9, 2010.
Dihydroorotase from the hyperthermophile, Aquifex aeolicus is activated by stoichiometric association with aspartate transcarbamoylase and forms a one-pot reactor for pyrimidine biosynthesis. Pengfei Zhang, Philip D. Martin, Cristina Purcarea, Asmita Vaishnav, Joseph S. Brunzelle, Roshini Fernando, Hedeel I. Guy-Evans, David R. Evans and Brian F.P. Edwards. (2009) Biochemistry, 48, 766–78.
Invited Book Chapter: Mammalian Aspartate Transcarbamoylase in “Aspartate Transcarbamoylase (ed. Guy Hervé) Nova Press, (2009)
The sole Serine/Threonine Protein Kinase and its cognate phosphatase from Aquifex Aeolicus Targets Pyrimidine Biosynthesis. Cristina Purcarea, Roshini Fernando, Hedeel Guy-Evans and David R. Evans (2008) Molecular Cellular Biochem, Apr;311(1–2):199–213.
Protein Kinase A Phosphorylation of the Multifunctional Protein CAD Antagonizes Activation by the MAP Kinase Cascade. Damian H. Kotsis, Elizabeth M. Masko, Frederic D. Sigoillot, Roberto Di Gregorio, Hedeel I. Guy-Evans and David R. Evans (2007) Molecular Cellular Biochem. Jul; 301(1–2):69–81.
Protein Kinase C modulates the upregulation of the pyrimidine biosynthetic complex, CAD, by MAP kinase. Frederic D. Sigoillot, Damian H. Kotsis, Elizabeth M. Masko, Monica Bame, David R. Evans, Hedeel Guy Evans (2007) Front. Biosci. 12: 3892–3898.
The Crystal Structure of a Novel, Latent Dihydroorotase from Aquifex aeolicus at 1.7 A Resolution. Philip I. Martin, Cristina Purcarea, Pengfei Zhang, Asmita Vaishnav, Sharon Sadecki, Hedeel I. Guy-Evans, David R. Evans and Brian F. P. Edwards (2005) J. Mol. Biol. 348:535–47.
Nuclear localization of the multifunctional protein CAD phosphorylated by the MAP kinase cascade. Frederic D. Sigoillot, Damian H. Kotsis, Valerie Serre, Severine M. Sigoillot, David R. Evans and Hedeel I. Guy (2005) J. Biol. Chem. 280, 25611-25620.
Recipient of the 2019 Ronald W. Collins Distinguished Faculty Research Award