Kenneth B. Marcu, Ph.D.

Emeritus Professor

Biochemistry and Cell Biology Dept.

Life Sciences Rm#330

 

Bologna, Italy Lab
Ioannina, Greece Lab

• Research Description

  Research 

  Research Description:

  As of January 1, 2016, I retired from my full time Professorial position and am now an Emeritus Professor at Stony Brook University. Thus I no longer have my own laboratory or research group at Stony Brook and am also no longer an active member of any graduate programs. In my retirement I am also only residing at my family home in Bologna, Italy and will only be returning to the USA ~3 times each year mostly to see my family and also visit the laboratories of my remaining scientific collaborators at Stony Brook (Prof. Richard Kew in Pathology), Manhattan, NY (Dr. Miguel Otero at the Hospital for Special Surgery) and California (Prof. Roland Wolkowicz at San Diego State Univ. and Dr. David Habiel at the Cedars Cancer Institute in Los Angeles). In addition, I will also continue to direct, co-direct or function as a senior advisor of basic biomedical research projects at other research institutes in Europe (where I also hold either Adjunct or Affiliated Appointments) on a year round basis including:  (1) My longstanding collaboration on mechanisms associated with Osteoarthritic disease onset and progression  with Drs. Eleonora Olivotto and Rosy Borzi at the Rizzoli Orthopedic Research Institute (affiliated with the University of Bologna in Bologna, Italy); (2) The IMBB-FORTH Biomedical Research Institute.  IMBB-FORTH (Ioannina Univ. Medical School, Ioannina, Greece) with my colleague Prof. Vagelis Kolettas; (3) The Biomedical Research Foundation Academy of Athens (BRFAA) in Athens. Greece with my colleagues Drs. Apostolos Klinakis, Dimitris Thanos and Evangelos Andreakos.  Overall, my research projects will continue to involve the regulation and mechanisms of action of the inhibitor of NF-kappaB kinase (IKK) complex. The IKK signaling complex is essential for the activation of the NF-kappaB transcription factor family. Moreover, the IKKbeta and IKKalpha serine threonine kinases in the IKK signalsome also functionally impact on a number of other NF-kappaB independent growth and differentiation pathways in various cell types. IKKbeta and IKKalpha are orchestrators of developmental and inflammatory processes including all stress-like responses, innate and adaptive immunity and the survival and growth of normal and malignant cells. Together with colleagues and collaborators in the States and Europe I have been exploring the functional roles and mechanisms of action of IKKalpha and IKKbeta in different disease-related biological contexts including:  (1) novel cell migration responses specifically elicited in response to tissue damage and mediators of sepsis which initially invokes a pronounced inflammatory reaction that can eventually give way to tissue repair in part via the recruitment of progenitor, stem cells, (2) gene expression and epigenomic regulation associated with the maintenance of articular chondrocyte homeostasis and/or differentiation programming towards hypertrophy along with mechanical and pro-inflammatory stress that can lead to osteoarthritic disease, (3) alterations in gene expression programming in response to specific forms of extracellular stress including pro-inflammatory oncogenic events leading to DNA damage and premature cellular senescence and (4) specific alterations in cellular physiology that occur in cancer cell genesis and progression using both murine and human models of non-small-cell lung cancer onset and progression.

• Publications

  • Selected publications (from a total of 162) 

    Valbuena, O., Marcu, K., Weigert M. and Perry, R.P. (1978). The Multiplicity of Germ Line Genes Specifying a Group of Related Mouse Kappa Chains With Implications for the Generation of Immunoglobulin Diversity.  Nature 276, 780-784.

    Schibler, U., Marcu, K. and Perry, R.P. (1978). The Synthesis and Processing of the Messenger RNAs Specifying Heavy and Light Chain Immunoglobulins in MPC-11 Cells.  Cell l5, 1495-1509. 

    Marcu, K.B., Schibler, U. and Perry, R.P. (1979). The Nuclear Transcripts of Mouse Heavy Chain Immunoglobulin Contain Only the Expressed Class of C-region Sequences.  Science 241, 1087-1088. 

    Tucker, P., Marcu, K., Slightom, J. and Blattner, F. (1979). Structure of the Constant and 3' Untranslated Regions of the Murine g2b Heavy Chain mRNA.  Science 206, 1299-1303. 

    Tucker, P., Marcu, K., Newell, N. Richards, J. and Blattner, F. (1979). Sequence of the Cloned Gene for the Constant Region of Murine g2b Immunoglobulin Heavy Chain. Science 206, 1303-1306. 

    Marcu, K.B., Banerji, J., Penncavage, N., Lang, R. and Arnheim, N. (1980). The 5' Flanking Region of Immunoglobulin Heavy Chain Constant Region Genes Displays Length Heterogeneity in the Germ Lines of Inbred Mouse Strains.  Cell 22, 187-196. 

    Harris, L.J., Lang, R.B. and Marcu, K.B. (1982). Non-immunoglobulin Associated DNA Rearrangements in Mouse Plasmacytomas.  Proc. Natl. Acad. Sci. USA 79, 4175-4179. 

    Marcu, K.B., Lang, R.B., Stanton, L.W. and Harris, L.J. (1982). A Model for the Molecular Requirements of Immunoglobulin Heavy Chain Class Switching.  Nature 298, 87 89. 

    Marcu, K.B. and Cooper, M. (1982). New Views of the Immunoglobulin Heavy-chain Switch.  Nature 298, 327-328. 

    Marcu, K.B. (1982). Immunoglobulin Heavy Chain Constant Region Genes.  Cell 29, 719-721. 

    Stanton, L.W., Watt, R. and Marcu, K.B. (1983). Translocation, Breakage and Truncated Transcripts of the c-myc Oncogene in Murine Plasmacytomas.  Nature 303, 401-406. 

    Stanton, L.W., Fahrlander, P.D., Tesser, P.C. and Marcu, K.B. (1984). Nucleotide Sequence Comparison of Normal and Translocated Murine c-myc Genes.  Nature 310, 423-425. 

    Piechaczyk, M., Yang, J.Q., Blanchard, J., Jeanteur, Ph. and Marcu, K.B. (1985).  Post-Transcriptional Mechanisms are Responsible for Accumulation of Truncated c-myc RNAs in Murine Plasma Cell Tumors.  Cell 42, 589-597. 

    Nepveu, A., Fahrlander, P.D., Yang, J.Q. and Marcu, K.B. (1985). Amplification and Altered Expression of the c-myc Oncogene in A-MuLV Transformed Fibroblasts. Nature 317, 440-443. 

    Fahrlander, P.D., Piechaczyk, M. and Marcu, K.B. (1985). Chromatin Structure of the Murine c-myc Locus: Implications for the Regulation of Normal and Chromosomally Translocated Genes.  EMBO J. 4, 3195-3202. 

    Nepveu, A. and Marcu, K.B. (1986). Intragenic Pausing and Anti-sense Transcription Within the Murine c-myc Locus.  EMBO J. 5, 2859-2865.                                                      

     

    Ott, D.E., Alt, F.W. and Marcu, K.B. (1987). Immunoglobulin Heavy Chain Switch Region Recombination Within a Retroviral Vector in Murine pre-B Cells.  EMBO J. 6, 577-584. 

    Bossone, S.A., Asselin, C., Patel, A.J. and Marcu, K.B. (1992). MAZ, a Novel Zinc Finger Protein Binds to c-myc and C2 Gene Sequences Regulating Transcriptional Initiation and Termination.  Proc. Natl. Acad. Sci. USA 89, 7452-7456. 

    Marcu, K.B., Bossone, S.A. and Patel, A.J. (1992). MYC Regulation and Function.  Ann. Rev. Biochem. 61, 809-860. 

    Ballantyne, J., Henry, D.L., Briere, F., Mueller, J., Kehry, M., Snapper, C. and Marcu, K.B. (1998) Efficient recombination of a switch substrate retrovector in CD40 activated B lymphocytes: Implications for the regulation of the IgCH switch-recombinase. J. Immunol. 161, 1336-1347. 

    McKenzie, F.R., Connelly, M.A., Balzarano, D., Müller, J.R., Geleziunas, R. and Marcu, K.B. (2000) Functional isoforms of IKKa (IkB-kinase-a) lacking leucine zipper and helix-loop-helix domains reveal that IKKa and IKKb have different activation requirements. Mol. Cell. Biol. 20: 2635-2649. 

     Li, J., Peet, G.W., Balzarano, D., Li, X., Massa, P., Barton, R. and Marcu, K.B. (2001) Novel NEMO/IKKg and NF-kB target genes at the pre-B to immature B cell transition. J. Biol. Chem. 276: 18579-18590. 

     Li, X., Massa, P., Hanidu, A., Peet, G.W., Aro, P., Savitt, A., Mische, S. Li, J. and Marcu, K.B. (2002) IKKa, IKKb and NEMO/IKKg are each required for the NF-kB mediated inflammatory response program. J. Biol. Chem. 277: 45129-45140. 

    Massa, P.E., Li, X., Hanidu, A., Siamas, J., Pariali, M., Pareja, J., Savitt, A.G., Catron,   K.M., Li, J., and Marcu, K.B. (2005). Gene expression profiling in conjunction with physiological rescues of IKKa null cells with Wt. or mutant IKKa reveals distinct classes of IKKa/NF-kB dependent genes. J. Biol. Chem. 280:  14057-14069 

     

    Palumbo, R., Glavez, B.G., Pusterla, T., De Marchis, F., Cossu, G., Marcu, K.B. and Bianchi, M.E. (2007). Cells migrating to sites of tissue damage in response to the danger signal HMGB1 require NF-kB activation. J. Cell Biol. 179:  33-40 

    Sansone, P., Storci, G-L., Tavolari, S.,Guarnieri, T., Giovannini, C., Taffurelli, M., Ceccarelli, C., Santini, D., Paterini, P., Marcu, K.B., Chieco^, P., and Bonafe, M. (2007). Interleukin-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland.  J. Clinical Investigation 117: 3988-4002. 

    Olivotto, E., Borzi', R.M., Vitellozzi, R., Pagani, S., Facchini, A., Battistelli, M., Penzo, M., Li, X., Flamigni, F., Li, J., Falcieri, E., Facchini, A.,  and Marcu, K.B. (2008) Differential requirements for IKKa and IKKb in the differentiation of primary human osteoarthritic chondrocytes.  Arthritis and Rheumatism 58: 227-239. 

    Penzo, M., Massa, P.E., Olivotto, Bianchi. F., Borzi, R.M., Hanidu, A., Li, X., Li. J. and  Marcu, K.B. (2009).   Sustained NF-kB activation produces a short-term cell proliferation block in conjunction with repressing effectors of cell cycle progression controlled by E2F or FoxM1. J. Cellular Physiology 218: 215-227.  

    Batsi. C., Markopoulou, S., Kontargiris, E., Charalambous, C. Thomas, C., Christoforidis, S., Kanavaros, P.  Constantinou, A.I., Marcu^, K.B. and Kolettas, E. (2009). Bcl-2 blocks 2-methoxyestradiol induced leukemia cell apoptosis by a p27Kip1-dependent G1/S cell cycle arrest in conjunction with NF-kB.  Biochemical Pharmacology 78: 33-44. 

    Batsi, C., Markopoulou, A., Vartholomatos, G., Georgiou, I., Kanavaros, P., Gorgoulis, V.C., Marcu, K.B. and Kolettas, K. 2009. Chronic NF-kB activation delays RasV12-induced premature senescence of human fibroblasts by suppressing the DNA damage checkpoint response. Mechanisms of Aging and Development 130: 409-419.

     

    Marcu, KB, Otero, M., Olivotto, E., Borzi, R-M. and Goldring, M.B. (2010). NF-kB Signaling:  Multiple angles to target OA. In Innovative Drug Targets for Osteoarthritis Therapy. Current Drug Targets 11 (5): 599-613.

     

    Penzo, M., Molteni, R., Suda, T., Samaniego, S., Raucci, A., Habiel, D.M., Miller, F., Jiang, H-P., Li, J.., Pardi, R., Palumbo, R., Olivotto, E., Kew, R.R., Bianchi, M. and Marcu, K.B. 2010. Inhibitor of NF-{kappa}B Kinases {alpha} and {beta} are both essential for High Mobility Group Box 1-mediated chemotaxis. J. of Immunol 184 (8): 4497-4509.

     

    Borzi, R-M., Olivotto, E., Pagani, S., Vitellozzi, R., Neri, S., Battistelli, M., Falcieri, E., Facchini, A., Flamigni, F., Penzo, M., Platano, D., Santi, S., Facchini, A. and Marcu, K. B. 2010. Matrix metalloproteinase 13 loss associated with impaired ECM remodeling disrupts chondrocyte differentiation by concerted effects on multiple regulatory factors. Arthristis and Rheumatism 62: 2370-2381.

     

    Storci, G., Sansone, P., Mari, S., D’Uva, G., Tavolari, S., Guarnirei, T., Taffurellli, M.,   

    Ceccarelli, C., Santini, D., Cheico, P., Marcu, K.B., Bonafe, M. 2010. TNFa up-regulates  SLUG via the NF-kB/HIF1alpha axis, which imparts breast cancer cells with a stem cell-like phenotype. J. Cell Physiol. 225:  682-691.

     

    Goldring, M.B., Otero^, M., Plumb, D.A., Dragomir, C., Favero, M., El Hachem, K., Hashimoto, K.,  Roach, H.I., Olivotto, E., Borzi, R-M.,  and Marcu, K.B.  2011. Roles of Inflammatory and anabolic cytokines in cartilage cytokine in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis.  European Cells and Materials Journal 21:  202-220.

    Goldring, M.B. and Marcu, K.B. 2012. Epigenomic and microRNA-mediated regulation in cartilage development, homeostasis, and osteoarthritis.  Trends in Molecular Medicine  18(2): 109-118

     

    Kew, R.R., Penzo. M., Habiel, D. M. and Marcu, K. B. 2012. The IKKa-dependent NF-kB p52/RelB non-canonical pathway is essential to sustain a CXCL12 autocrine loop in cells migrating in response to HMGB1. Journal of Immunology 188 (5): 2380-2386. PMCID: PMC3288724

     

    Sfikasa, A., C. Batsia, E. Tselikoua, G. Vartholomatosc, N. Monokrousosd, P. Pappase, S. Christoforidisf, T. Tzavarash, P. Kanavarosb, V.G. Gorgoulisi, K.B. Marcu, and E. Kolettas. 2012. The canonical NF-κB pathway differentially protects normal and human tumor cells from ROS-induced DNA damage. Cellular Signaling 24 (11): 2007-2023. PMCID: PMC3432746.

     

     Samaniego S, Marcu KB (2013) IKKβ in Myeloid Cells Controls the Host  Response to  Lethal and Sublethal Francisella tularensis LVS Infection. PLoS ONE  8(1): e54124.  doi:10.1371/journal.pone.0054124.

     

    Olivotto, E., Miguel Otero, M., Astolfi, A. Platano, D., Facchini, A. Pagani, S., Flamigni, F., Facchini, A., Goldring, M.B., Borzì, R.M., and Marcu, K.B. (2013). IKKalpha/CHUK regulates extracellular matrix remodeling independent of its kinase activity to facilitate articular chondrocyte differentiation. PLOS ONE 8(9): e73024.  

     

    Penzo, M,, Habiel, D.M., Ramadass, M., Kew, R. R. and Marcu, K.B. (2014). Cell migration to CXCL12 reuires simultaneous IKKalpha and IKKbeta-dependent NF-kB signaling.  BBA-Mol.Cell Res. 1843 (9): 1796-1804.

     

    Olivotto, E., Otero^, M., Marcu^, KB and Goldring^, MB (2015). Pathophysiology of  Osteoarthritis:Canonical NF-kappaB/IKKbeta-dependent and kinase independent effects of IKKalpha in Cartilage Degradation and Chondrocyte Differentiation.  RMD Open 1:e000061.doi:10.1136/rmdopen- 

     

    Santana, A., Oldenburg, D., Kirillov, V., Malik, L., Do ng, Q., Sinayev, R., Marcu, K.B.,

    White, D., and Krug, L. (2017).  LPS/TLR4 signaling enhances RTA occupancy of the origin of lytic replication during murine gammaherpesvirus 68 reactivation from latency. Pathogens Feb 16;6(1). pii: E9. doi: 10.3390/pathogens6010009.

     

    Markopoulos, G.S., Roupakin, E., Tokamani, M., Chavdoula, E., Marcu, K.B., Papavassiliou, A., Sandaltzopoulos, R. and Kolettas, E.  (2017).  “A step-by-stepmiRNA guide to cancer cell development and metastasis”, Cellular Oncology 40: 303-339.

     

    Markopoulos, G.S., Roupakin, E., Tokamani, M.,  Alabasi, G., Sandaltzopoulos, R.  Marcu,  K.B. and Kolettas, E. (2018) Roles of NF-kappaB signalling in the regulation of miRNAs impacting on inflammation in cancer.  Biomedicines (in press)

     

    Purva Singh^, P., Marcu^, K.B.,  Goldring^, M.B., and Otero^, M. (2018).  Phenotypic Instability of Chondrocytes in Osteroarthritis:  On a Path to Hypertrophy. Annals of NY Acad. of Sciences (in press)