Research Faculty


Nicholas J Donato, Ph.D.
Research Assistant Professor

ndonato@umich.edu
Phone: 734-615-5542

UM Comprehensive Cancer Center
Room 4306/SPC 5936
1500 E. Medical Center Dr.
Ann Arbor, MI 48103

Research Interests

Primary focus is on targeted therapy of hematologic malignancies and the description and validation of new therapeutic targets. Initial focus was on protein kinases and phosphatases as therapeutic targets. More recent studies involve definition of regulatory processes that control protein destruction and localization through modulation of ubiquitin ligases and deubiquitinases

Education and Training

June 1978 B.S., Biochemestry, University of California, Riverside, CA
Dec 1984 Ph.D., Biochemistry, University of California, College of Natural and Agricultural Sciences, Department of Biochemistry, Riverside, CA
Jan 1986 NIH Postdoctoral Fellow, Molecular and Cellular, Endocrinology Training Program, Dr. Anthony Norman, Director
Aug 1989 Research Associate, Immunopharmacology Section, Department of Clinical Immunology and Biological Therapy, M.D. Anderson Hospital and Tumor Institute, Houston, TX
   

Honors & Awards

2003-present Appointed Trustee, Balfour Medical Foundation
2003 HSC Honors Convocation Recipient
   


Selected Publications (2005-present)

    1. Johnson FM, Saigal B, Talpaz M, Donato NJ.  Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res, 2005 Oct 1; 11(19 Pt 1):6924-6932. (PMID 16203784)

    2. Gao H, Lee BN, Talpaz M, Donato NJ, Cortes JE, Kantarjian HM, Reuben JM.  Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia. Leukemia, 2005 Nov; 19(11):1905-1911. (PMID 16151467)

    3. Johnson FM, Saigal B, Donato NJ.  Induction of heparin-binding EGF-like growth factor and activation of EGF receptor in imatinib mesylate-treated squamous carcinoma cells. J Cell Physiol, 2005 Nov; 205(2):218-227. (PMID 15887238).

    4. Chandra J, Tracy J, Loegering D, Flatten K, Verstovsek S, Beran M, Gorre M, Estrov Z, Donato N, Talpaz M, Sawyers C, Bhalla K, Karp J, Sausville E, Kaufmann SH. Adaphostin-induced oxidative stress overcomes BCR/ABL mutation-dependent and -independent imatinib resistance. Blood, 2006 Mar 15; 107(6):2501-2506. (PMID 16291594)  PMC 1895739

    5. Trevino JG, Summy JM, Lesslie DP, Parikh NU, Hong DS, Lee FY, Donato NJ, Abbruzzese JL, Baker CH, Gallick GE.  Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol, 2006 Mar; 168(3):962-972. (PMID 16507911)  PMC 1606527.

    6. Klostergaard J, Leroux ME, Auzenne E, Khodadadian M, Spohn W, Wu JY, Donato NJ. Hyperthermia engages the intrinsic apoptotic pathway by enhancing upstream caspase activation to overcome apoptotic resistance in MCF-7 breast adenocarcinoma cells. J Cell Biochem, 2006 May 15; 98(2):356-369. (PMID 16440323).

    7. Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med, 2006 Jun 15; 354(24):2531-2541. (PMID 16775234).

    8. Ferrari-Amorotti G, Keeshan K, Zattoni M, Guerzoni C, Iotti G, Cattelani S, Donato NJ, Calabretta B. Leukemogenesis induced by wild-type and STI571-resistant BCR/ABL is potently suppressed by C/EBPalpha. Blood, 2006 Aug 15; 108(4):1353-1362. (PMID 16670262)  PMC 1895881

    9. Bartholomeusz G, Talpaz M, Bornmann W, Kong LY, Donato NJ.  Degrasyn activates proteasomal-dependent degradation of c-Myc. Cancer Res, 2007 Apr 15; 67(8):3912-3918. (PMID 17440106).

    10. Bartholomeusz GA, Talpaz M, Kapuria V, Kong LY, Wang S, Estrov Z, Priebe W, Wu J, Donato NJ. Activation of a novel Bcr/Abl destruction pathway by WP1130 induces apoptosis of chronic myelogenous leukemia cells. Blood, 2007 Apr 15; 109(8):3470-3478. (PMID 17202319)  PMC 1852235.

    11. Zinner RG, Nemunaitis J, Eiseman I, Shin HJ, Olson SC, Christensen J, Huang X, Lenehan PF, Donato NJ, Shin DM.  Phase I clinical and pharmacodynamic evaluation of oral CI-1033 in patients with refractory cancer. Clin Cancer Res, 2007 May 15; 13(10):3006-3014. (PMID 17505003).

    12. Johnson FM, Saigal B, Tran H, Donato NJ.  Abrogation of signal transducer and activator of transcription 3 reactivation after Src kinase inhibition results in synergistic antitumor effects. Clin Cancer Res, 2007 Jul 15; 13(14):4233-4244. (PMID 17634553).

    13. Mughal T, Cortes J, Cross NC, Donato N, Hantschel O, Jabbour E, Kantarjian H, Melo JV, Skorski T, Silver RT, Goldman JM.  Chronic myeloid leukemia--some topical issues. Leukemia, 2007 Jul; 21(7):1347-1352. (PMID 17495971).

    14. Wu J, Meng F, Lu H, Kong L, Bornmann W, Peng Z, Talpaz M, Donato NJ.  Lyn regulates BCR-ABL and Gab2 tyrosine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic myelogenous leukemia cells. Blood, 2008 Apr 1; 111(7):3821-3829. (PMID 18235045)  PMC 2275035.

    15. Quintas-Cardama A, Gibbons DL, Kantarjian H, Talpaz M, Donato N, Cortes J. Sequencing of subcloned PCR products facilitates earlier detection of BCR-ABL1(T315I) and other mutants compared to direct sequencing of the ABL1 kinase domain. Leukemia, 2008 Apr; 22(4):885-888. http://www.nature.com/leu/journal/v22/n4/full/leu200842a.html (PMID 18305550).

    16. Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, Darnay BG, Lamothe B, Sun H, Talpaz M, Donato NJ.  Association between imatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst, 2008 Jul 2; 100(13):926-939. (PMID 18577747)  PMC 2902818

    17. Soliera AR, Lidonnici MR, Ferrari-Amorotti G, Prisco M, Zhang Y, Martinez RV, Donato NJ, Calabretta B. Transcriptional repression of c-Myb and GATA-2 is involved in the biologic effects of C/EBPalpha in p210BCR/ABL-expressing cells. Blood, 2008 Sep 1; 112(5):1942-1950. (PMID 18550858)  PMC 2518896.

    18. Krijanovski Y, Donato N, Sun H, Meng F, Quintas-Cardama A, Cortes J, Talpaz M. Dasatinib resistance in patients with chronic mylogenous leukemia: identification of a novel bcr-abl kinase doman mutation. Clinical Leukemia, 2008 Nov; 2(4):267-271. doi: 10.3816/CLK.2008.n.037

    19. Pene-Dumitrescu T, Peterson LF, Donato NJ, Smithgall TE.  An inhibitor-resistant mutant of Hck protects CML cells against the antiproliferative and apoptotic effects of the broad-spectrum Src family kinase inhibitor A-419259. Oncogene, 2008 Nov 27; 27(56):7055-7069. (PMID 18794796)  PMC 2738638.

    20. Bellodi C, Lidonnici MR, Hamilton A, Helgason GV, Soliera AR, Ronchetti M, Galavotti S, Young KW, Selmi T, Yacobi R, Van Etten RA, Donato N, Hunter A, Dinsdale D, Tirro E, Vigneri P, Nicotera P, Dyer MJ, Holyoake T, Salomoni P, Calabretta B.  Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J Clin Invest, 2009 May; 119(5):1109-1123. (PMID 19363292)  PMC 2673867.

    21. Donato NJ, Fang D, Sun H, Giannola D, Peterson LF, Talpaz M.  Targets and effectors of the cellular response to aurora kinase inhibitor MK-0457 (VX-680) in imatinib sensitive and resistant chronic myelogenous leukemia. Biochem Pharmacol, 2010 Mar 1; 79(5):688-697. (PMID 19874801).

    22. Wu J, Meng F, Ying Y, Peng Z, Daniels L, Bornmann WG, Quintas-Cardama A, Roulston D, Talpaz M, Peterson LF, Donato NJ.  ON012380, a putative BCR-ABL kinase inhibitor with a unique mechanism of action in imatinib-resistant cells. Leukemia, 2010 Apr; 24(4):869-872. (PMID 20111070).

    23. Carayol N, Vakana E, Sassano A, Kaur S, Goussetis DJ, Glaser H, Druker BJ, Donato NJ, Altman JK, Barr S, Platanias LC.  Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci U S A, 2010 Jul 13; 107(28):12469-12474. (PMID 20616057)  PMC 906574.

    24. Lidonnici MR, Audia A, Soliera AR, Prisco M, Ferrari-Amorotti G, Waldron T, Donato N, Zhang Y, Martinez RV, Holyoake TL, Calabretta B.  Expression of the transcriptional repressor Gfi-1 is regulated by C/EBP{alpha} and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells. Cancer Res, 2010 Oct 15; 70(20):7949-7959. (PMID 20924107)  PMC 2955805.

    25. Kapuria V, Peterson LF, Fang D, Bornmann WG, Talpaz M, Donato NJ.  Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res, 2010 Nov 15; 70(22):9265-9276. (PMID 21045142) .

    26. Donato NJ, Peterson LF.  Chronic myeloid leukemia stem cells and developing therapies. Leuk Lymphoma, 2011 Feb; 52 Suppl 1:60-80. (PMID 21299460).

    27. Sun H, Kapuria V, Peterson LF, Fang D, Bornmann WG, Bartholomeusz G, Talpaz M, Donato NJ. Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. Blood 2011 Mar 17; 117(11):3151-3162. (PMID 21248063).

    28. Albajar M, Gomez-Casares MT, Llorca J, Mauleon I, Vaque JP, Acosta JC, Bermudez A, Donato N, Delgado MD, Leon J.  MYC in chronic myeloid leukemia: induction of aberrant DNA synthesis and association with poor response to imatinib. Mol Cancer Res, 2011 May; 9(5):564-576. (PMID 21460180).

    29. Peterson LF, Mitrikeska E, Giannola D, Lui Y, Sun H, Bixby D, Malek SN, Donato NJ, Wang S, Talpaz M. p53 stabilization induces apoptosis in chronic myeloid leukemia blast crisis cells. Leukemia, 2011 May; 25(5):761-769. (PMID 21350558).

    30. Kapuria V, Peterson LF, Showalter HD, Kirchhoff PD, Talpaz M, Donato NJ.  Protein cross-linking as a novel mechanism of action of a ubiquitin-activating enzyme inhibitor with anti-tumor activity. Biochem Pharmacol, 2011 Aug 15; 82(4):341-349. (PMID 21621524).

    31. Donato NJ. Bcr-Abl adds another twist to cell fate. Blood, 2011 Sep 8; 118(10):2646-2647. Commentary. (PMID 21903901).

    32. Donato NJ. Imatinib is receptive to a collaboration. Blood, 2011 Oct 13; 118(15):4009-4010. Commentary. (PMID 21998331).

    33. Burkholder KM, Perry JW, Wobus CE, Donato NJ, Showalter HD, Kapuria V, O'Riordan MX. A small molecule deubiquitinase inhibitor increases localization of inducible nitric oxide synthase to the macrophage phagosome and enhances bacterial killing. Infect Immun, 2011 Dec; 79(12):4850-4857. (PMID 21911458)  PMC 3232648.

    34. Peng Z, Pal A, Han D, Wang S, Maxwell D, Levitzki A, Talpaz M, Donato NJ, Bornmann W. Tyrphostin-like compounds with ubiquitin modulatory activity as possible therapeutic agents for multiple myeloma. Bioorg Med Chem, 2011 Dec 1; 19(23):7194-7204. (PMID 22036213).

    35. Kapuria V, Levitzki A, Bornmann WG, Maxwell D, Priebe W, Sorenson RJ, Showalter HD, Talpaz M, Donato NJ.  A novel small molecule deubiquitinase inhibitor blocks Jak2 signaling through Jak2 ubiquitination. Cell Signal, 2011 Dec; 23(12):2076-2085. (PMID 21855629).

    36. Vakana E, Altman JK, Glaser H, Donato NJ, Platanias LC.  Antileukemic effects of AMPK activators on BCR-ABL-expressing cells. Blood, 2011 Dec 8; 118(24):6399-6402. (PMID 22021366)  PMC 3236122.

    37. Perry JW, Ahmed M, Chang KO, Donato NJ, Showalter HD, Wobus CE.  Antiviral activity of a small molecule deubiquitinase inhibitor occurs via induction of the unfolded protein response. PLoS Pathog, 2012; 8(7):e1 002783. (PMID 22792064)  PMC 3390402.

    38. Peng Z, Maxwell D, Sun D, Pal A, Ying Y, Han D, Gao L, Wang S, Kapuria V, Talpaz M, Young M, Showalter HD, Donato NJ and Bornmann W.  Degrasyn-like Compounds with Deubiquitinase Inhibitory Activity as Possible Therapeutic Agents for Multiple Myeloma (MM-1). Bioorg Med Chem 2014 Feb 15;22(4):1450-8. doi: 10.1016/j.bmc.2013.12.048. Epub 2014 Jan 3. (PMID 24457091) PMC 24457091

    39. Gibbons D, Pricl S, Posocco P, Laurini E, Fermeglia M, Sun H, Talpaz M, Cortes J, Donato NJ and Quintas-Cardamas A. Molecular dynamics reveal BCR-ABL1 Polymutants as a Novel Mechanism of Resistance to pan-BCR-ABL1 Kinase Inhibitor Therapy. Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3550-5. doi: 10.1073/pnas.1321173111. Epub 2014 Feb 18. (PMID 24550512) PMC 3948238

    40. Gonzalez-Hernandez MJ, Pal A, Gyan KE, Charbonneau M-E, Showalter HD, Donato NJ, O’Riordan M and  Wobus CE. Chemical derivatives of a small molecule deubiquitinase inhibitor have broad spectrum antiviral activity against several RNA viruses. PLoS One. 2014 Apr 10;9(4):e94491. doi: 10.1371/journal.pone.0094491. eCollection 2014. (PMID 24722666) PMC 3983190

    41. Charbonneau ME, Gonzalez-Hernandez MJ, Showalter HD, Donato NJ, Wobus CE, O'Riordan MX. Small molecule deubiquitinase inhibitors promote macrophage anti-infective capacity. PLoS One. 2014 Aug 5;9(8):e104096. doi: 10.1371/journal.pone.0104096. eCollection 2014. (PMID 25093325) PMC 25093325

    42. Pal A, Young M and Donato NJ. Emerging Potential of Therapeutic Targeting of Ubiquitin Specific Proteases in the Treatment of Cancer. Cancer Res 2014 Sep 15;74(18):4955-4966. Epub 2014 Aug 29. Review. (PMID 25172741)

    43. Potu H, Peterson LF, Verhaegen M, Cao J, Talpaz M and Donato NJ. Usp5 Links Suppression of p53 and FAS Levels in Melanoma to the BRAF Pathway. Oncotarget, 2014 Jul 30;5(14):5559-69. (PMID 24980819) PMC 4170643

    44. Pal A and Donato NJ. Ubiquitin-Specific Proteases as therapeutic targets for treatment of breast cancer. Breast Cancer Research, in Press, October 2014.


     

     

    Updated Oct 2014