Dr Michael Cahill
Areas of expertise
- Biochemistry And Cell Biology 3101
- Receptors And Membrane Biology 310110
- Cell Metabolism 310103
- Signal Transduction 310111
- Protein Trafficking 310108
- Cancer Cell Biology 321101
- Oncology And Carcinogenesis 3211
- Neurosciences 3209
- Proteomics And Intermolecular Interactions (Excl. Medical Proteomics) 310109
- Medical Biochemistry Proteins And Peptides (Incl. Medical Proteomics) 320506
- Evolutionary Biology 3104
Research interests
I have used a multidisciplinary suite of methods to characterise the cell and organism biology of the protein Progesterone Receptor Membrane Component 1 (PGRMC1) and related proteins. These range from Omics platforms (proteomics, metabolomics, genomics, methylomics in recent publications) to phylogenetic studies to identify which amino acids are the most functionally conserved in evolution, which is a surrogate for identifying residues involved in important cellular functions.
PGRMC1 is involved in diverse cell and organism processes, ranging from metabolism and migration to membrane trafficking and steroid biology. In 2022 I published a unifying model which proposes that PGRMC-like proteins were critical for both the regulation of mitochondrial metabolism during the endosymbiotic origin of eukaryotes, and also for the origin of the eumetazoan animal gastrulation organiser and its subsequent mechanism of defining new differentiated tissue types. The last common eumetazoan ancestor (LEUMCA) was the first organism to develop cells specialised for as nerves, muscle, insulogenic secretion, or photoreception. These were accompanied in evolution by the concomitant acquisition of a novel PGRMC C-terminus and new phosphorylated tyrosines. Mutation of PGRMC phosphorylated amino acids exerts profound effects over the epigenetic landscape, in patterns resembling those of early embryogenesis and tissue differentiation. Therefore PGRMC phosphorylated tyrosines were acquired in evolution just before complex body plans began to be specified by the gastrulation organiser, and may be a part of the mechanism by which differentiated cell identity is specified and/or maintained. See my recent publications for details.
PGRMC1 may also be centrally involved in the mechanism of Alzheimer's disease, being directly involved in the mechanism of action of novel synaptorestorative anti-Alzheimer's therapeutics that improve cognition in animal studies and are currently undergoing human Phase 2 trials. See my 2022 'Quo vadis' publication for details.
Biography
I obtained a BSc in Zoology and Biochemistry with the University of New South Wales, and moved to Germany for a PhD in the group of Alfred Nordheim at the Medizinische Hochschule Hannover (MHH). I remained in Germany for a total of almost the first 18 years of my postgraduate career, during which time I followed a career path through signal transduction and transcriptional regulation during my PhD and Postdoctoral time, into developing proteomics technologies, and applying those new technologies to biological conditions - especially cancer - at ProteoSys AG (Mainz), a German Biotechnology company that I co-founded (2000 - 2007) as a spin-off from the University of Tübingen Institute for Molecular Biology. During this time I successfully acquired >3.5 million Euros in grants from German national and European international agencies through the University of Tübingen and ProteoSys AG.
Among the many hundreds of proteomics discoveries at ProteoSys was the observation that the then obscure protein Progesterone Receptor Membrane Component 1 (PGRMC1) was differentially phosphorylated in breast cancers of differing morbidity. Perplexingly, it was attested to have a wide range of seemingly unrelated functions under different pseudonyms from different animals (see my 2007 review). Because the company chose not to pursue PGRMC1, I decided to relocate back to my native Australia to pursue what I considered to be this crown jewel of the company proteomics portfolio in the research dynamics of an academic environment.
In 2008 I moved back to Australia to Charles Sturt University at Wagga Wagga, NSW, as an academic with teaching and research responsibilities. I taught biochemistry and cell biology and pursued my research into PGRMC1 until I left by my own choice in January 2021 because, despite a successful European track record and a vigorous series of grant applications (30 grants between 2008 and 2020), I was never awarded a dollar in national competitive grant funds. This was despite hindsight showing that PGRMC1 was indeed an important protein in different ways for eukaryotic and animal biology, especially in metabolism, cancer biology, and neuronal differentiation status: e.g., it is probably a key point in the mechanism of Alzheimer's disease (see my 2022 reviews, especially the 'Quo Vadis" publication). That has led to my role as scientific advisor for Cognition Therapeutics Inc. (Pittsburgh, PA, USA) in 2013.They developed a novel synaptorestorative molecule to clear Alzheimer's neuronal synapses of oligomeric amyloid beta, which improves cognition in animal models and is currently in Phase 2 clinical trials. The mechanism involves a membrane trafficking function of PGRMC1.
I have been an Honorary academic associated with the Hannan Laboratory at The John Curtin School of Medical Research since 7 January 2019.
Publications
- Thejer, B, Infantino, V, Santarsiero, A et al. 2023, 'Sigma-2 Receptor Ligand Binding Modulates Association between TSPO and TMEM97', International Journal of Molecular Sciences, vol. 24, no. 7, pp. 1-20.
- Miles, N, Hicksb , K, Nelson, K et al. 2023, 'Finding flow: unpacking the capacity of in-lecture question activities to engage online students', Technology, Pedagogy and Education, vol. 32, no. 2, pp. 71-190.
- Cahill, M 2022, 'Quo vadis PGRMC? Grand-Scale Biology in Human Health and Disease', Frontiers in Bioscience - Landmark, vol. 27, no. 11.
- Cahill, M 2022, 'Unde venisti PGRMC? Grand-Scale Biology from Early Eukaryotes and Eumetazoan Animal Origins', Frontiers in Bioscience-Landmark (FBL), vol. 27, no. 11.
- Teakel, S, Marama, M, Aragão, D et al. 2022, 'Structural characterization of a MAPR-related archaeal cytochrome b5M protein', FEBS Letters, vol. 596, no. 18, pp. 2409-2417.
- Bai, Y, Ludescher, M, Poschmann, G et al. 2021, 'PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling', Cancers, vol. 13, no. 22, pp. 1-22.
- Izzo , N, Colom-Cadena, M, Riad, A et al. 2020, 'Proceedings from the Fourth International Symposium on σ-2 Receptors: Role in Health and Disease', eNeuro, vol. 7, no. 6, pp. 1-7.
- Thejer, B, Adhikary, P, Kaur, A et al. 2020, 'PGRMC1 phosphorylation affects cell shape, motility, glycolysis, mitochondrial form and function, and tumor growth', BMC Molecular and Cell Biology, vol. 21, no. 1, pp. -.
- Thejer, B, Adhikary, P, Teakel, S et al. 2020, 'PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease', BMC Molecular and Cell Biology, vol. 21, no. 1, pp. 1-19.
- Hehenberger, E, Eitel, M, Fortunato, S et al. 2020, 'Early eukaryotic origins and metazoan elaboration of MAPR family proteins', Molecular Phylogenetics and Evolution, vol. 148, pp. 1-15.
- Teakel, S, Ludescher, M, Thejer, B et al. 2020, 'Protein complexes including PGRMC1 and actin-associated proteins are disrupted by AG-205', Biochemical and Biophysical Research Communications, vol. 524, no. 1, pp. 64-69.
- Wang, X, Mahajan, H, Dickinson, N et al. 2018, 'Fine needle aspiration biopsy cytology of phyllodes tumour and fibroadenoma: A cytomorphological study of 104 cases', Diagnostic Cytopathology, vol. 46, no. 11, pp. 927-935.
- Cahill, M 2017, 'The evolutionary appearance of signaling motifs in PGRMC1', BioScience Trends, vol. 11, no. 2, pp. 179-192.
- Cahill, M & Medlock, A 2017, 'Thoughts on interactions between PGRMC1 and diverse attested and potential hydrophobic ligands', Journal of Steroid Biochemistry and Molecular Biology, vol. 171, pp. 11-33.
- Cahill, M, Jazayeri, J, Catalano, S et al. 2016, 'The emerging role of progesterone receptor membrane component 1 (PGRMC1) in cancer biology', Biochimica et Biophysica Acta - Reviews on Cancer, vol. 1866, no. 2, pp. 339-349.
- Cahill, M, Jazayeri, J, Kovacevic, Z et al. 2016, 'PGRMC1 regulation by phosphorylation: Potential new insights in controlling biological activity!', Oncotarget, vol. 7, no. 32, pp. 50822-50827.
- Gosnell, M, Anwer, A, Mahbub, S et al. 2016, 'Quantitative non-invasive cell characterisation and discrimination based on multispectral autofluorescence features', Scientific Reports, vol. 6.
- Gosnell, M, Anwer, A, Cassano, J et al. 2016, 'Non-invasive detection and monitoring of biochemistry in cells and tissues by decomposing autofluorescence', 2016 Asia Communications and Photonics Conference, ACP 2016, Optical Society of America (OSA), United States.
- Drozdowicz-Tomsia, K, Anwer, A, Cahill, M et al. 2014, 'Multiphoton fluorescence lifetime imaging microscopy reveals free-to-bound NADH ratio changes associated with metabolic inhibition', Journal of Biomedical Optics, vol. 19, no. 8.
- J. Izzo, N, Xu, J, Zeng, C et al. 2014, 'Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity', PLOS ONE (Public Library of Science), vol. 9, no. 11.
- Neubauer, H, Ruan, X, Schneck, H et al. 2013, 'Overexpression of progesterone receptor membrane component 1: Possible mechanism for increased breast cancer risk with norethisterone in hormone therapy', Menopause, vol. 20, no. 5, pp. 504-510.
- Zhou, J, Yu, Q, Chen, R et al. 2013, 'Medroxyprogesterone acetate-driven increase in breast cancer risk might be mediated via cross-talk with growth factors in the presence of progesterone receptor membrane component-1', Maturitas, vol. 76, no. 2, pp. 129-133.
- Schneck, H, Ruan, X, Seeger, H et al. 2013, 'Membrane-receptor initiated proliferative effects of dienogest in human breast cancer cells', Gynecological Endocrinology, vol. 29, no. 2, pp. 160-162.
- Ruan, X, Schneck, H, Schultz, S et al. 2012, 'Nomegestrol acetate sequentially or continuously combined to estradiol did not negatively affect membrane-receptor associated progestogenic effects in human breast cancer cells', Gynecological Endocrinology, vol. 28, no. 11, pp. 863-866.
- Ruan, X, Neubaue, H, Yang, Y et al. 2012, 'Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells', Climacteric, vol. 15, no. 5, pp. 467-472.
- Neubauer, H, Yang, Y, Seeger, H et al. 2011, 'The presence of a membrane-bound progesterone receptor sensitizes the estradiol-induced effect on the proliferation of human breast cancer cells', Menopause, vol. 18, no. 8, pp. 845-850.
- Neubauer, H, Chen, R, Schneck, H et al. 2011, 'New insight on a possible mechanism of progestogens in terms of breast cancer risk', Hormone Molecular Biology and Clinical Investigation, vol. 6, no. 1, pp. 185-192.
- J. Bryant, K, J. Bidgood, M, Lei, P et al. 2011, 'A Bifunctional Role for Group IIA Secreted Phospholipase A2 in Human Rheumatoid Fibroblast-like Synoviocyte Arachidonic Acid Metabolism', Journal of Biological Chemistry, vol. 286, no. 4, pp. 2492-2502.
- Neubauer, H, Adam, G, Seeger, H et al. 2009, 'Membrane-initiated effects of progesterone on proliferation and activation of VEGF in breast cancer cells', Climacteric, vol. 12, no. 3, pp. 230-239.
- Langer, R, Ott, K, Specht, K et al. 2008, 'Protein expression profiling in esophageal adenocarcinoma patients indicates association of heat-shock protein 27 expression and chemotherapy response', Clinical Cancer Research, vol. 14, no. 24, pp. 8279-8287.
- Neubauer, H, E Clare, S, Wozny, W et al. 2008, 'Breast cancer proteomics reveals correlation between estrogen receptor status and differential phosphorylation of PGRMC1', Breast Cancer Research, vol. 10, no. 5.
- Cahill, M 2007, 'Progesterone receptor membrane component 1: An integrative review', Journal of Steroid Biochemistry and Molecular Biology, vol. 105, no. 1-5, pp. 16-36.
- Neubauer, H, Fehm, T, Schütz, C et al. 2007, 'Proteomic expression profiling of breast cancer', Recent results in cancer research. Fortschritte der Krebsforschung. Progre`s dans les recherches sur le cancer, vol. 176, pp. 89-120.
- Cahill, M, Vogt, J, Servos, J et al. 2007, 'Metabolically stable isotope labeling prior to electrophoretic protein separation reveals differences in fractional synthesis rates between mitochondrial aldehyde dehydrogenase isoforms', Journal of Chromatography A, vol. 1161, no. 1-2, pp. 67-70.
- Wozny, W, Schroer, K, Schwall, G et al. 2007, 'Differential radioactive quantification of protein abundance ratios between benign and malignant prostate tissues: Cancer association of annexin A3', Proteomics, vol. 7, no. 2, pp. 313-322.
- Neubauer, H, E. Clare, S, Kurek, R et al. 2006, 'Breast cancer proteomics by laser capture microdissection, sample pooling, 54-cm IPG IEF, and differential iodine radioisotope detection', Electrophoresis, vol. 27, no. 9, pp. 1840-1852.
- Hunzinger, C, Wozny, W, Schwall, G et al. 2006, 'Comparative profiling of the mammalian mitochondrial proteome: Multiple aconitase-2 isoforms including N-formylkynurenine modifications as part of a protein biomarker signature for reactive oxidative species', Journal of Proteome Research, vol. 5, no. 3, pp. 625-633.
- A. Vogt, J, Hunzinger, C, Schroer, K et al. 2005, 'Determination of Fractional Synthesis Rates of Mouse Hepatic Proteins via Metabolic 13C-Labeling, MALDI-TOF MS and Analysis of Relative Isotopologue Abundances Using Average Masses', Analytical Chemistry, vol. 77, no. 7, pp. 2034-2042.
- Poznanovic, S, Wozny, W, Schwall, G et al. 2005, 'Differential radioactive proteomic analysis of microdissected renal cell carcinoma tissue by 54 cm isoelectric focusing in serial immobilized pH gradient gels', Journal of Proteome Research, vol. 4, no. 6, pp. 2117-2125.
- Poznanovic, S, Schwall, G, Zengerling, H et al. 2005, 'Isoelectric focusing in serial immobilized pH gradient gels to improve protein separation in proteomic analysis', Electrophoresis, vol. 26, no. 16, pp. 3185-3190.
- Cahill, M, Schrattenholz, A, Wozny, W et al. 2005, 'Differential and quantitative molecular analysis of ischemia complexity reduction by isotopic labeling of proteins using a neural embryonic stem cell model', Third International Congress on Vascular Dementia, ed. A.D. Korczyn, P. Kalvach, N.D. Bornstein, Elsevier, Online, pp. 261-267.
- Schrattenholz, A, Klemm, M & Cahill, M 2004, 'Potential of comprehensive toxico-proteomics: Quantitative and differential mining of functional proteomes from native samples', ATLA Alternatives to Laboratory Animals, vol. 32, no. 1, pp. 123-131.
- Davezac, N, Tondelier, D, Lipecka, J et al. 2004, 'Global proteomic approach unmasks involvement of keratins 8 and 18 in the delivery of cystic fibrosis transmembrane conductance regulator (CFTR)/ΔF508-CFTR to the plasma membrane', Proteomics, vol. 4, no. 12, pp. 3833-3844.
- Vogt, J, Schroer, K, Holzer, K et al. 2003, 'Protein abundance quantification in embryonic stem cells using incomplete metabolic labelling with 15N amino acids, matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry, and analysis of relative isotopologue abundances of peptides', Rapid Communications in Mass Spectrometry, vol. 17, no. 12, pp. 1273-1282.
- Poland, J, Cahill, M & Sinha, P 2003, 'Isoelectric focusing in long immobilized pH gradient gels to improve protein separation in proteomic analysis', Electrophoresis, vol. 24, no. 7-8, pp. 1271-1275.
- Cahill, M, Wozny, W, Schwall, G et al. 2003, 'Analysis of relative isotopologue abundances for quantitative profiling of complex protein mixtures labelled with the acrylamide/D3-acrylamide alkylation tag system', Rapid Communications in Mass Spectrometry, vol. 17, no. 12, pp. 1283-1290.
- Vuong, G, Weiss, S, Kammer, W et al. 2000, 'Improved sensitivity proteomics by postharvest alkylation and radioactive labeling of proteins', Electrophoresis, vol. 21, no. 13, pp. 2594-2605.
- Heidenreich, O, Neininger, A, Schratt, G et al. 1999, 'MAPKAP kinase 2 phosphorylates serum response factor in vitro and in vivo', Journal of Biological Chemistry, vol. 274, no. 20, pp. 14434-14443.
- Cahill, M 1997, 'c-Fos transrepression revisited', FEBS Letters, vol. 400, no. 1, pp. 9-10.
- M. Müller, J, Cahill, M, A. Rupec, R et al. 1997, 'Antioxidants as well as oxidants activate c-fos via Ras-dependent activation of extracellular-signal-regulated kinase 2 and Elk-1', European Journal of Biochemistry, vol. 244, no. 1, pp. 45-52.
- Cahill, M, Peter, M, Kischkel, F et al. 1996, 'CD95 (APO-1/Fas) induces activation of SAP kinases downstream of ICE-like proteases', Oncogene, vol. 13, no. 10, pp. 2087-2096.
- Cahill, M, Nordheim, A & Xu, Y 1996, 'Crosslinking of SRF to the c-fos SRE CArG box guanines using photo-active thioguanine oligodeoxynucleotides', Biochemical and Biophysical Research Communications, vol. 229, no. 1, pp. 170-175.
- Cahill, M, Janknecht, R & Nordheim, A 1996, 'Signalling pathways: Jack of all cascades', Current Biology, vol. 6, no. 1, pp. 16-19.
- M. Müller, J, Cahill, M, Nordheim, A et al. 1996, 'The transcription factor TCF/Elk-1: A nuclear sensor of changes in the cellular redox status', in Robert Snyder, I. Glenn Sipes, David J. Jollow, Terrence J. Monks, James J. Kocs (ed.), Biological Reactive Intermediates V, Springer New York, New York, pp. 77-84.
- Ernst, W, Janknecht, R, Cahill, M et al. 1995, 'Transcriptional repression mediated by the serum response factor', FEBS Letters, vol. 357, no. 1, pp. 45-49.
- Zinck, R, Cahill, M, Kracht, M et al. 1995, 'Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and stress-activated protein kinase pathways that converge on Elk-1', Molecular and Cellular Biology, vol. 15, no. 9, pp. 4930-4938.
- Cahill, M, Ernst, W, Janknecht, R et al. 1994, 'Regulatory squelching', FEBS Letters, vol. 344, no. 2-3, pp. 105-108.
- Cahill, M, Nordheim, A & Janknecht, R 1994, 'Co-occurrence of CArG boxes and TCF sites within viral genomes', Biochemical and Biophysical Research Communications, vol. 205, no. 1, pp. 545-551.
