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John Krolewski

TitleProfessor
InstitutionSchool of Medicine and Dentistry
DepartmentPathology and Laboratory Medicine
AddressUniversity of Rochester Medical Center
School of Medicine and Dentistry
601 Elmwood Ave, Box 626
Rochester NY 14642
 
 Overview
The first part of Dr. Krolewski's career was driven by his discovery of Tyk2, the first member of the JAK family of tyrosine kinases. Working in collaboration with others, he linked Tyk2 to the interferon-alpha receptor, helped characterize the mechanism of 'broken receptor' signaling, and also the role of intra-membrane proteolysis in interferon signaling.

Subsequently, he re-focused his interests on the mechanisms of androgen withdrawal induced apoptosis of prostate epithelial cancer cells, with an emphasis on the role of cytokine signaling downstream of androgens. He has been investigating androgen regulation of the caspase inhibitor FLIP (CFLAR) and a paracrine cytokine network (TNF, TGFß) that is responsible for triggering epithelial cell death. Understanding this mechanism may enable the development of novel nanoparticle therapies for prostate cancer (currently under development with Y. Kwon, UC Irvine). He has collaborated with imaging scientists to develop and employ small animal MRI to measure prostate volume enabling his group to use KO mice to demonstrate that androgen withdrawal induced apoptosis requires TNF and TGFß signaling. He is currently participating in a multi-disciplinary collaboration (radiology, imaging physics, optics, electrical engineering, chemistry) to develop molecular imaging probes for photoacoustic imaging of early prostate cancer. He has other ongoing collaborations to develop microfluidic devices for SDS-PAGE (M. Bachman, G.P. Li, UC Irvine).

Dr, Krolewski's research has been continuously funded by the National Cancer Institute since 1992, in addition to other agencies (DOD, National Multiple Sclerosis Society, CA Dept of Health Sciences and the University of CA).

 
 Selected Publications
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  1. Saedinia S, Nastiuk KL, Krolewski JJ, Li GP, Bachman M. Laminated microfluidic system for small sample protein analysis. Biomicrofluidics. 2014 Jan; 8(1):014107.
    View in: PubMed
  2. Pioli PD, Saleh AM, El Fiky A, Nastiuk KL, Krolewski JJ. Sequential proteolytic processing of an interferon-alpha receptor subunit by TNF-alpha converting enzyme and presenilins. J Interferon Cytokine Res. 2012 Jul; 32(7):312-25.
    View in: PubMed
  3. Davis JS, Nastiuk KL, Krolewski JJ. TNF is necessary for castration-induced prostate regression, whereas TRAIL and FasL are dispensable. Mol Endocrinol. 2011 Apr; 25(4):611-20.
    View in: PubMed
  4. Yoo KS, Nastiuk KL, Krolewski JJ. Transforming growth factor beta1 induces apoptosis by suppressing FLICE-like inhibitory protein in DU145 prostate epithelial cells. Int J Cancer. 2009 Feb 15; 124(4):834-42.
    View in: PubMed
  5. Nastiuk KL, Krolewski JJ. FLIP-ping out: death receptor signaling in the prostate. Cancer Biol Ther. 2008 Aug; 7(8):1171-9.
    View in: PubMed
  6. Cornforth AN, Davis JS, Khanifar E, Nastiuk KL, Krolewski JJ. FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells. Oncogene. 2008 Jul 24; 27(32):4422-33.
    View in: PubMed
  7. El Fiky A, Pioli P, Azam A, Yoo K, Nastiuk KL, Krolewski JJ. Nuclear transit of the intracellular domain of the interferon receptor subunit IFNaR2 requires Stat2 and Irf9. Cell Signal. 2008 Jul; 20(7):1400-8.
    View in: PubMed
  8. Nastiuk KL, Yoo K, Lo K, Su K, Yeung P, Kutaka J, Danielpour D, Krolewski JJ. FLICE-like inhibitory protein blocks transforming growth factor beta 1-induced caspase activation and apoptosis in prostate epithelial cells. Mol Cancer Res. 2008 Feb; 6(2):231-42.
    View in: PubMed
  9. Nastiuk KL, Liu H, Hamamura M, Muftuler LT, Nalcioglu O, Krolewski JJ. In vivo MRI volumetric measurement of prostate regression and growth in mice. BMC Urol. 2007; 7:12.
    View in: PubMed
  10. Saleh AZ, Greenman KL, Billings S, Van Vranken DL, Krolewski JJ. Binding of madindoline A to the extracellular domain of gp130. Biochemistry. 2005 Aug 16; 44(32):10822-7.
    View in: PubMed
  11. El Fiky A, Arch AE, Krolewski JJ. Intracellular domain of the IFNaR2 interferon receptor subunit mediates transcription via Stat2. J Cell Physiol. 2005 Aug; 204(2):567-73.
    View in: PubMed
  12. Krolewski JJ. Cytokine and growth factor receptors in the nucleus: what's up with that? J Cell Biochem. 2005 Jun 1; 95(3):478-87.
    View in: PubMed
  13. Saleh AZ, Fang AT, Arch AE, Neupane D, El Fiky A, Krolewski JJ. Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor. Oncogene. 2004 Sep 16; 23(42):7076-86.
    View in: PubMed
  14. Kumar KG, Krolewski JJ, Fuchs SY. Phosphorylation and specific ubiquitin acceptor sites are required for ubiquitination and degradation of the IFNAR1 subunit of type I interferon receptor. J Biol Chem. 2004 Nov 5; 279(45):46614-20.
    View in: PubMed
  15. Nastiuk KL, Kim JW, Mann M, Krolewski JJ. Androgen regulation of FLICE-like inhibitory protein gene expression in the rat prostate. J Cell Physiol. 2003 Aug; 196(2):386-93.
    View in: PubMed
  16. Saleh AZ, Nguyen VP, Krolewski JJ. Affinity of Stat2 for the subunits of the interferon alpha receptor. Biochemistry. 2002 Sep 17; 41(37):11261-8.
    View in: PubMed
  17. Nguyen VP, Saleh AZ, Arch AE, Yan H, Piazza F, Kim J, Krolewski JJ. Stat2 binding to the interferon-alpha receptor 2 subunit is not required for interferon-alpha signaling. J Biol Chem. 2002 Mar 22; 277(12):9713-21.
    View in: PubMed
  18. Lukashova V, Asselin C, Krolewski JJ, Rola-Pleszczynski M, Stanková J. G-protein-independent activation of Tyk2 by the platelet-activating factor receptor. J Biol Chem. 2001 Jun 29; 276(26):24113-21.
    View in: PubMed
  19. Zhang Y, Turkson J, Carter-Su C, Smithgall T, Levitzki A, Kraker A, Krolewski JJ, Medveczky P, Jove R. Activation of Stat3 in v-Src-transformed fibroblasts requires cooperation of Jak1 kinase activity. J Biol Chem. 2000 Aug 11; 275(32):24935-44.
    View in: PubMed
  20. Nastiuk KL, Mansukhani M, Terry MB, Kularatne P, Rubin MA, Melamed J, Gammon MD, Ittmann M, Krolewski JJ. Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate. 1999 Aug 1; 40(3):172-7.
    View in: PubMed
  21. Printz DJ, Strauss DH, Goetz R, Sadiq S, Malaspina D, Krolewski J, Gorman JM. Elevation of CD5+ B lymphocytes in schizophrenia. Biol Psychiatry. 1999 Jul 1; 46(1):110-8.
    View in: PubMed
  22. Danial NN, Losman JA, Lu T, Yip N, Krishnan K, Krolewski J, Goff SP, Wang JY, Rothman PB. Direct interaction of Jak1 and v-Abl is required for v-Abl-induced activation of STATs and proliferation. Mol Cell Biol. 1998 Nov; 18(11):6795-804.
    View in: PubMed
  23. Krishnan K, Singh B, Krolewski JJ. Identification of amino acid residues critical for the Src-homology 2 domain-dependent docking of Stat2 to the interferon alpha receptor. J Biol Chem. 1998 Jul 31; 273(31):19495-501.
    View in: PubMed
  24. Yan H, Piazza F, Krishnan K, Pine R, Krolewski JJ. Definition of the interferon-alpha receptor-binding domain on the TYK2 kinase. J Biol Chem. 1998 Feb 13; 273(7):4046-51.
    View in: PubMed
  25. Singh B, Ittmann MM, Krolewski JJ. Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus. Genes Chromosomes Cancer. 1998 Feb; 21(2):166-71.
    View in: PubMed
  26. Domanski P, Fish E, Nadeau OW, Witte M, Platanias LC, Yan H, Krolewski J, Pitha P, Colamonici OR. A region of the beta subunit of the interferon alpha receptor different from box 1 interacts with Jak1 and is sufficient to activate the Jak-Stat pathway and induce an antiviral state. J Biol Chem. 1997 Oct 17; 272(42):26388-93.
    View in: PubMed
  27. Mansukhani MM, Nastiuk KL, Hibshoosh H, Kularatne P, Russo D, Krolewski JJ. Convenient, nonradioactive, heteroduplex-based methods for identifying recurrent mutations in the BRCA1 and BRCA2 genes. Diagn Mol Pathol. 1997 Aug; 6(4):229-37.
    View in: PubMed
  28. Stancato LF, Sakatsume M, David M, Dent P, Dong F, Petricoin EF, Krolewski JJ, Silvennoinen O, Saharinen P, Pierce J, Marshall CJ, Sturgill T, Finbloom DS, Larner AC. Beta interferon and oncostatin M activate Raf-1 and mitogen-activated protein kinase through a JAK1-dependent pathway. Mol Cell Biol. 1997 Jul; 17(7):3833-40.
    View in: PubMed
  29. Krishnan K, Pine R, Krolewski JJ. Kinase-deficient forms of Jak1 and Tyk2 inhibit interferon alpha signaling in a dominant manner. Eur J Biochem. 1997 Jul 1; 247(1):298-305.
    View in: PubMed
  30. Uddin S, Sweet M, Colamonici OR, Krolewski JJ, Platanias LC. The vav proto-oncogene product (p95vav) interacts with the Tyk-2 protein tyrosine kinase. FEBS Lett. 1997 Feb 10; 403(1):31-4.
    View in: PubMed
  31. Krishnan K, Yan H, Lim JT, Krolewski JJ. Dimerization of a chimeric CD4-interferon-alpha receptor reconstitutes the signaling events preceding STAT phosphorylation. Oncogene. 1996 Jul 4; 13(1):125-33.
    View in: PubMed
  32. Eilers A, Kanda K, Klose B, Krolewski J, Decker T. Constitutive STAT1 tyrosine phosphorylation in U937 monocytes overexpressing the TYK2 protein tyrosine kinase does not induce gene transcription. Cell Growth Differ. 1996 Jun; 7(6):833-40.
    View in: PubMed
  33. Yan H, Krishnan K, Lim JT, Contillo LG, Krolewski JJ. Molecular characterization of an alpha interferon receptor 1 subunit (IFNaR1) domain required for TYK2 binding and signal transduction. Mol Cell Biol. 1996 May; 16(5):2074-82.
    View in: PubMed
  34. Gupta S, Yan H, Wong LH, Ralph S, Krolewski J, Schindler C. The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction of IFN-alpha signals. EMBO J. 1996 Mar 1; 15(5):1075-84.
    View in: PubMed
  35. Yan H, Krishnan K, Greenlund AC, Gupta S, Lim JT, Schreiber RD, Schindler CW, Krolewski JJ. Phosphorylated interferon-alpha receptor 1 subunit (IFNaR1) acts as a docking site for the latent form of the 113 kDa STAT2 protein. EMBO J. 1996 Mar 1; 15(5):1064-74.
    View in: PubMed
  36. Davis E, Krishnan K, Yan H, Newcomb EW, Krolewski JJ. A mutant form of p135tyk2, an interferon-alpha inducible tyrosine kinase, suppresses the transformed phenotype of Daudi cells. Leukemia. 1996 Mar; 10(3):543-51.
    View in: PubMed
  37. Domanski P, Yan H, Witte MM, Krolewski J, Colamonici OR. Homodimerization and intermolecular tyrosine phosphorylation of the Tyk-2 tyrosine kinase. FEBS Lett. 1995 Nov 6; 374(3):317-22.
    View in: PubMed
  38. Yan H, Lim JT, Contillo LG, Krolewski JJ. Glutathione S-transferase fusion proteins mimic receptor dimerization in permeabilized cells. Anal Biochem. 1995 Nov 1; 231(2):455-8.
    View in: PubMed
  39. Yetter A, Uddin S, Krolewski JJ, Jiao H, Yi T, Platanias LC. Association of the interferon-dependent tyrosine kinase Tyk-2 with the hematopoietic cell phosphatase. J Biol Chem. 1995 Aug 4; 270(31):18179-82.
    View in: PubMed
  40. Greenlund AC, Morales MO, Viviano BL, Yan H, Krolewski J, Schreiber RD. Stat recruitment by tyrosine-phosphorylated cytokine receptors: an ordered reversible affinity-driven process. Immunity. 1995 Jun; 2(6):677-87.
    View in: PubMed
  41. Colamonici O, Yan H, Domanski P, Handa R, Smalley D, Mullersman J, Witte M, Krishnan K, Krolewski J. Direct binding to and tyrosine phosphorylation of the alpha subunit of the type I interferon receptor by p135tyk2 tyrosine kinase. Mol Cell Biol. 1994 Dec; 14(12):8133-42.
    View in: PubMed
  42. Ittmann M, Wieczorek R, Heller P, Dave A, Provet J, Krolewski J. Alterations in the p53 and MDM-2 genes are infrequent in clinically localized, stage B prostate adenocarcinomas. Am J Pathol. 1994 Aug; 145(2):287-93.
    View in: PubMed
  43. Colamonici OR, Domanski P, Krolewski JJ, Fu XY, Reich NC, Pfeffer LM, Sweet ME, Platanias LC. Interferon alpha (IFN alpha) signaling in cells expressing the variant form of the type I IFN receptor. J Biol Chem. 1994 Feb 25; 269(8):5660-5.
    View in: PubMed
  44. Colamonici OR, Uyttendaele H, Domanski P, Yan H, Krolewski JJ. p135tyk2, an interferon-alpha-activated tyrosine kinase, is physically associated with an interferon-alpha receptor. J Biol Chem. 1994 Feb 4; 269(5):3518-22.
    View in: PubMed
  45. Krolewski JJ, Dalla-Favera R. The ltk gene encodes a novel receptor-type protein tyrosine kinase. EMBO J. 1991 Oct; 10(10):2911-9.
    View in: PubMed
  46. Firmbach-Kraft I, Byers M, Shows T, Dalla-Favera R, Krolewski JJ. tyk2, prototype of a novel class of non-receptor tyrosine kinase genes. Oncogene. 1990 Sep; 5(9):1329-36.
    View in: PubMed
  47. Krolewski JJ, Lee R, Eddy R, Shows TB, Dalla-Favera R. Identification and chromosomal mapping of new human tyrosine kinase genes. Oncogene. 1990 Mar; 5(3):277-82.
    View in: PubMed
  48. Smereczynski A, Krolewski J, Krzysztalowksi A. [Developmental anomalies of the cranio-cervical region]. Chir Narzadow Ruchu Ortop Pol. 1990; 55(4-6):293-7.
    View in: PubMed
  49. Krolewski JJ, Dalla-Favera R. Molecular genetic approaches in the diagnosis and classification of lymphoid malignancies. Hematol Pathol. 1989; 3(2):45-61.
    View in: PubMed
  50. Krolewski JJ, Rush MG. Some extrachromosomal circular DNAs containing the Alu family of dispersed repetitive sequences may be reverse transcripts. J Mol Biol. 1984 Mar 25; 174(1):31-40.
    View in: PubMed
  51. Krolewski JJ, Schindler CW, Rush MG. Structure of extrachromosomal circular DNAs containing both the Alu family of dispersed repetitive sequences and other regions of chromosomal DNA. J Mol Biol. 1984 Mar 25; 174(1):41-54.
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  52. Schindler CW, Krolewski JJ, Rush MG. Selective trapping of circular double-stranded DNA molecules in solidifying agarose. Plasmid. 1982 May; 7(3):263-70.
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  53. Krolewski JJ, Bertelsen AH, Humayun MZ, Rush MG. Members of the Alu family of interspersed, repetitive DNA sequences are in the small circular DNA population of monkey cells grown in culture. J Mol Biol. 1982 Jan 25; 154(3):399-415.
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  54. Krolewski JJ, Murphy E, Novick RP, Rush MG. Site-specificity of the chromosomal insertion of Staphylococcus aureus transposon Tn554. J Mol Biol. 1981 Oct 15; 152(1):19-33.
    View in: PubMed
  55. Novick RP, Khan SA, Murphy E, Iordanescu S, Edelman I, Krolewski J, Rush M. Hitchhiking transposons and other mobile genetic elements and site-specific recombination systems in Staphylococcus aureus. Cold Spring Harb Symp Quant Biol. 1981; 45 Pt 1:67-76.
    View in: PubMed
  56. Skopek TR, Liber HL, Krolewski JJ, Thilly WG. Quantitative forward mutation assay in Salmonella typhimurium using 8-azaguanine resistance as a genetic marker. Proc Natl Acad Sci U S A. 1978 Jan; 75(1):410-4.
    View in: PubMed
  57. Deluca JG, Krolewski J, Skopek TR, Kaden DA, Thilly WG. 9-Aminoacridine-A frameshift mutagen for Salmonella typhimurium TA 1537 inactive at the hgprt locus in human lymphoblasts. Mutat Res. 1977 Feb; 42(2):327-30.
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  58. Deluca JG, Kaden DA, Krolewski J, Skopek TR, Thilly WG. Comparative mutagenicity of ICR-191 to S. typhimurium and diploid human lymphoblasts. Mutat Res. 1977 Feb 1; 46(1):11-8.
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  59. Bogutyn W, Krolewski J. [Deformations in the Klippel-Trenaunay syndrome]. Chir Narzadow Ruchu Ortop Pol. 1972; 37(3):398-403.
    View in: PubMed

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