I am a chemist by training and my laboratory has been a cancer biology laboratory for years (see Molecular Cancer Research Cover Art from a recent publication of a graduate student in the laboratory). Traditionally, cancer and neurodegenerative diseases have been considered at the opposite end of the spectrum of human diseases; cancer is characterized by highly dividing cells that resist death while neurodegenerative diseases are associated with death of post-mitotic cells. Today, genetic and cell biology studies show multiple common pathways in cancer and neurodegeneration. This includes pathways that regulate microtubule (MT) stability in cells.
Proper regulation of MT stability is fundamental for neuronal functions and many neurodegenerative diseases are caused or characterized by altered MT dynamics. This is the case of Alzheimer’s disease (AD) and other neurological diseases called tauophathies, where hyperphosphorylation of the MT stabilizing protein Tau, leads to loss of MT mass in the brain.
Mine is among a handful of labs around the world to study a protein called UNC-45A. UNC-45A is a member of UCS domain family highly conserved throughout evolution. Despite its ubiquitousness and conservation, still little is known about its mechanisms of action. We have discovered that UNC-45A, is a key regulator of cytoskeletal functions in mammalian cells, including: a) cytokinesis b) exocytosis in immune cells, and c) axonal growth via regulation of acto-myosin contractility. In addition to UNC-45A’s role in the regulation of acto-myosin system we recently found that UNC-45A is also a novel Microtubule-Associated Protein (MAP) with MT destabilizing activity (see TIRF microscope image of UNC-45 bound to MT).
We are interested in understanding whether and how UNC-45A (see UNC-45A expression in brain) contributes to AD. Our working hypothesis is that UNC-45A is a MT lattice destabilizing protein which is overexpressed in AD and contributes to its initiation and progression. Understanding the molecular mechanisms that regulate neuronal MT mass is significant for targeted therapies for AD.
Because we believe that successful collaborations are at the core of scientific discovery, we have partnered with scientists and researchers across the University, and other national and international institutions. In our investigations we employ the state of the art and cutting-edge reagents and techniques and use clinical specimens of human diseases.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
- Deubiquitinating Enzymes in Coronaviruses and Possible Therapeutic Opportunities for COVID-19.Clemente V, D'Arcy P, Bazzaro M. Int J Mol Sci. 2020 May 15;21(10). Cover Art.
- Drug Development Targeting the Ubiquitin-Proteasome System (UPS) for the Treatment of Human Cancers. Zhang X, Linder S, Bazzaro M. Cancers (Basel). 2020 Apr 7;12(4):902.
- UNC-45A is preferentially expressed in epithelial cells and binds to and co-localizes with interphase MTs. Habicht J, Mooneyham A, Shetty M, Zhang X, Shridhar V, Winterhoff B, Zhang Y, Cepela J, Starr T, Lou E, Bazzaro M. Cancer Biol Ther. 2019;20(10):1304-1313.
- Targeting Mitochondria for Treatment of Chemoresistant Ovarian Cancer. Emmings E, Mullany S, Chang Z, Landen CN Jr, Linder S, Bazzaro M. Int J Mol Sci. 2019 Jan 8;20(1).
- UNC-45A Is a Novel Microtubule-Associated Protein and Regulator of Paclitaxel Sensitivity in Ovarian Cancer Cells. Mooneyham A, Iizuka Y, Yang Q, Coombes C, McClellan M, Shridhar V, Emmings E, Shetty M, Chen L, Ai T, Meints J, Lee MK, Gardner M, Bazzaro M. Mol Cancer Res. 2019. Cover Art.
- RNA Sequencing of Carboplatin- and Paclitaxel-Resistant Endometrial Cancer Cells Reveals New Stratification Markers and Molecular Targets for Cancer Treatment. Hellweg R, Mooneyham A, Chang Z, Shetty M, Emmings E, Iizuka Y, Clark C, Starr T, Abrahante JH, Schütz F, Konecny G, Argenta P, Bazzaro M. Horm Cancer. 2018 Oct;9(5):326-337. Cover Art
- UNC-45A is required for neurite extension via controlling NMII activation. Iizuka Y, Mooneyham A, Sieben A, Chen K, Maile M, Hellweg R, Schütz F, Teckle K, Starr T, Thayanithy V, Vogel RI, Lou E, Lee MK, Bazzaro M. Mol Biol Cell. 2017 May 15;28(10):1337-1346.
- USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment. Vogel RI, Pulver T, Heilmann W, Mooneyham A, Mullany S, Zhao X, Shahi M, Richter J, Klein M, Chen L, Ding R, Konecny G, Kommoss S, Winterhoff B, Ghebre R, Bazzaro M. Oncotarget. 2016 May 24;7(21):30962-76.
- UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion. Iizuka Y, Cichocki F, Sieben A, Sforza F, Karim R, Coughlin K, Isaksson Vogel R, Gavioli R, McCullar V, Lenvik T, Lee M, Miller J, Bazzaro M. J Immunol. 2015 Nov 15;195(10):4760-70.
- Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses. Coughlin K, Anchoori R, Iizuka Y, Meints J, MacNeill L, Vogel RI, Orlowski RZ, Lee MK, Roden RB, Bazzaro M. Clin Cancer Res. 2014 Jun 15;20(12):3174-86.
- Myosin II co-chaperone general cell UNC-45 overexpression is associated with ovarian cancer, rapid proliferation, and motility. Bazzaro M, Santillan A, Lin Z, Tang T, Lee MK, Bristow RE, Shih IeM, Roden RB. Am J Pathol. 2007 Nov;171(5):1640-9. doi: 10.2353/ajpath.2007.070325. Epub 2007 Sep 14. PMID: 17872978 Free PMC article.