GRUPOS DE INVESTIGACIÓN DEL IBBTEC
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Nombre del grupo:
Control Transcripcional y Cáncer
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Investigadora principal :
Dr. Javier Leon, Catedrático de Universidad
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Otro personal:
Dr. M. Dolores Delgado, Prof. Titular de Universidad
Dr. Eva García-Alegría, JAE-doc
Dr. Ana Batlle, postdoctoral
Juan M. Caraballo, becario predoctoral
Andrea Quintanilla, becaria predoctoral
M. Carmen Lafita, becaria predoctoral
Cristina Abraira, becaria predoctoral
Pilar Frade, técnico de laboratorio
Rosa Blanco, técnico de laboratorio
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Página web:
http://grupos.unican.es/bmCancer/
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Temas de investigación:
o Funciones de la oncoproteína MYC en el control de la diferenciación celular y
en leucemia. Interacciones de MYC con reguladores del ciclo celular p21 y p27
o Función de los reguladores transcripcionales CTCF y CTCF-L (BORIS) en la
diferenciación hematopoyética normal y patológica
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Financiación:
o “Red Cooperativa de Investigación en Cancer” ISCIII-RETIC-RD06/0020/0017,
IP: Javier León
o El regulador transcripcional CTCF: funciones en transcripción de genes
ribosomales, diferenciación y leucemia. Instituto de Salud Carlos III. FIS. 08/0829. IP:
M. Dolores Delgado
o Análisis molecular y funcional de la oncoproteína MYC como inhibidora de la
diferenciación celular. Ministerio de Ciencia e Innovación SAF08-01581. I.P.: Javier
León.
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Publicaciones relevantes (últimos 10 años)
o Albajar, M., Gómez-Casares, M.T., Llorca, J., Mauleon, J., Vaqué, J.P., Acosta, J.C.,
Bermúdez, A., Donato, N., Delgado, M.D. and León, J. MYC in chronic myeloid leukemia:
induction of aberrant DNA synthesis and association with poor response to imatinib. Mol
Cancer Res (2011) in press
o Bretones, G., Acosta J.C:, Caraballo, J., Ferrandiz, N., Gómez-Casares, M.T., Albajar, M.,
Blanco, R., Ruiz, P., Hung, W-C., Albero, M.P., Perez-Roger, I. and León J. Skp2 oncogene is a
direct Myc target gene and Myc downregulates p27kip1 through Skp2 in human leukemia
cells. J Biol Chem. (2011) 286: 9815-25
o Van de Nobelen, S., Rosa-Garrido, M., Leers, J., Heath, H., Soochit, W., Joosen,
L., Jonkers, I., Demmers, J., Van der Reijden, M., Torrano, V., Grosveld, F., Delgado,
M.D., Renkawitz, R., ,Galjart, N..and Sleutels, F. “CTCF regulates the local epigenetic
state of ribosomal DNA repeats”. Epigenetics and Chromatin (2010) 3:19.
o Agúndez,L., Machón,C., César, C.E., l Rosa-Garrido,M., Delgado, M.D., and
Llosa, M.* Nuclear targeting of a bacterial integrase which mediates site-specific
recombination between bacterial and human target sequences. Appl Env Miicrobiol
(2011) 77:201-210.
o Delgado, M.D and León, J. Myc roles in hematopoiesis and leukemia. Genes
&Cancer (2010) 1: 605–616. Review
o Ferrandiz, N, Caraballo, J. M., Albajar, M, Gomez-Casares, M.T., López-Jorge,
C.E., Blanco, R., Delgado, M.D. and Leon, J. p21Cip1 confers resistance to imatinib in
human chronic myeloid leukemia cells. Cancer Lett (2010) 292: 133-139.
o León J, Ferrándiz, N, Acosta, JC, Delgado, MD. Inhibition of cell differentiation:
a critical mechanism for MYC-mediated carcinogenesis? Cell Cycle (2009) 8: 1148-1157.
Review.
o Marques-Garcia F, Ferrandiz N, Fernandez-Alonso R, Gonzalez-Cano L,
Herreros-Villanueva M, Rosa-Garrido M, Fernandez-Garcia B, Vaque JP, Marques MM,
Alonso ME, Segovia JC, Leon J, Marin MC. p73 plays a role in erythroid differentiation
through GATA1 induction. J Biol Chem. (2009) 284: 21139-21156.
o Ferrandiz, N., Martin-Perez, J., Blanco, R, Donertas, D, Weber, A, Eilers, M,
Dotto, P, Delgado, M.D. and Leon, J. HCT116 cells deficient in p21Waf1 are
hypersensitive to tyrosine kinase inhibitors and adriamycin through a mechanism
unrelated to p21 and dependent on p53. DNA Repair (2009) 8: 390-399.
o López C, Ajenjo N, Muñoz-Alonso MJ, Frade P, León J, Gómez-Cimiano J.
Determination of viability of human cartilage allografts by a rapid and quantitative
method not requiring cartilage digestion. Cell Transplant. (2008) 17:859-64.
o Acosta, J. C., Ferrándiz, N., Bretones, G., Blanco.,R., Torrano, V., Richard,C., O’Conell,
B., Sedivy, J., Delgado, M.D., León, J. Myc inhibits p27-induced erythroid differentiation of
leukemia cells by repressing erythroid master genes without reversing the p27-mediated cell
cycle arrest. Mol Cell Biol (2008) 28: 7286-7295.
o Parreño,M., Casanova, I.,Céspedes, M.V., Vaqué, J.P.,Pavón,M.A., Leon, J. and
Mangues, R.Bobel-24 and derivatives induce Caspase-Independent Death in Pancreatic
Cancer, regardless of Apoptotic Resistance. Cancer Res (2008) 68:6313-23.
o Albajar, M. Gutierrez, P., Richard, C., Rosa-Garrido, M., Gómez-Casares, M.T.,
Steegmann, J.L. León, J. and Delgado M. D. PU.1 expression is restored upon treatment
of chronic myeloid leukemia patients. Cancer Lett (2008) 270, 328-336.
o Vaqué, JP., Fernández-García, B, García-Sanz, P., Ferrandiz, N., Bretones, G.,
Calvo, F., Crespo, P., Marín, M.C. and León, J. C-Myc inhibits Ras-mediated
differentiation of pheochromocytoma cells by blocking c-Jun up-regulation. Mol
Cancer Res. (2008) 6:325-339. PDF
o Renaud, S; Pugacheva, E; Delgado, M. D; Braunschweig, R; Abdullaev, Z;
Loukinov, D Benhattar, J; Lobanenkov, V. Expression of the CTCF-paralogous CancerTestis Gene, Brother Of the Regulator of Imprinted Sites (BORIS), Is Regulated by Three
Alternative Promoters Modulated by CpG-methylation and by CTCF and p53
Transcription Factors. Nuc Acids Res (2007)35: 7372–7388
o Sancho, P, Galeano, E, Nieto, E, Delgado , M.D. and García-Pérez, A.I.
Dequalinium induces cell death in human leukemia cells by early mitochondrial
alterations which enhance ROS production. Leuk Res (2007) 31:969-978.
o Fernandez-Garcia, B., Vaqué, J.P., Herreros-Villanueva, M., F Marques-Garcia1,
Castrillo, F., Fernandez-Medarde, A., León, J. and Marín, M.C. p73 cooperates with Ras
in the activation of MAP kinase signaling cascade. Cell Death Diff. 14:254-265 (2007).
PDF
o Delgado, M.D. and León, J. “Gene expression regulation and cancer”. Clinical &
Translational Oncology (2006) 8:780-787.PDF
o D’Arcy, V, Abdullaev, Z., Pore, N.,Docquier, F., Torrano, V., Chernukhin, I.,
Smart, M., Farrar, D., Metodiev, M., Fernandez, N., Richard, C., Delgado, M.D.,
Lobanenkov, V., Klenova, E. The Potential of BORIS detected in the leukocytes of breast
cancer patients as an early marker of tumourigenesis. Clinical Cancer Research
12:5978-5986.(2006).
o Parreño, M., Vaqué, J.P., Casanova, I., Frade, P, Céspedes, M.V., Pavón, M.A.,
Molins, A., Camacho, M., Vila, L., Nomdedeu, J.F., Mangues, R., and León, J. Novel
triiodo-phenol derivatives induce caspase-independent mitochondrial cell death in
leukemia cells which is inhibited by Myc. Mol. Cancer Ther. 5:1166-1175 (2006). PDF
o Torrano, V., Navascués, J., Docquier,F., Zhang, R., Burke, L., Chernukhin,I.,
Farrar, D., León, J., Berciano, M.T., Renkawitz, R., Klenova, E., Lafarga, M. and Delgado,
M.D. Targeting of CTCF to the nucleolus inhibits nucleolar transcription through a
poly(ADP-ribosyl)ation-dependent mechanism. J. Cell Science 119:1746-1759 (2006).
o Torrano,V.,Chernukhin, I., Docquier, F., D’Arcy, V., Leon, J., Klenova, E., and
Delgado, M.D. CTCF regulates growth and erythroid differentiation of human myeloid
leukemia cells. J.Biol. Chem. 280: 28152-28161 (2005). PDF
o Galeano, E., Nieto, E., García-Pérez, A.I., Delgado, M.D., Pinilla, M. and Sancho,
P. Effects of the antitumoural dequalinium on NB4 and K562 human leukemia cell
lines. Mitochondrial implication in cell death. Leukemia Research 29: 1201-1211(2005).
PDF
o Ceballos, E., Muñoz-Alonso, M.J., Berwanger, B, Acosta, J.C., Hernández, R.,
Krause, M., Hartman, O., Eilers, M. and León, J. Inhibitory effect of c-Myc on p53induced apoptosis in leukemia cells. Microarray analysis reveals defective induction of
p53 target genes and up-regulation of chaperone genes. Oncogene 24: 4559-4571
(2005). PDF
o Muñoz-Alonso, M.J., Acosta, J.C., Richard, C., Delgado, M.D., Sedivy, J. and
LeónJ. p21cip1 and p27kip1 induce distinct cell cycle effects and differentiation
programs in myeloid leukemia cells. J. Biol. Chem. 280: 18120-18129 (2005) PDF
o Vaqué, J.P., Navascués, J., Shiio, Y., Laiho, M., Ajenjo, N., Mauleon, I.,
Matallanas, D., Crespo, P. and León, J. Myc antagonizes Ras-mediated growth arrest in
leukemia cells through the inhibition of the Ras-Erk-p21Cip1 pathway. J.Biol. Chem.
280: 1112-22 (2005) PDF
o Ajenjo, N., Cañón, E., Sánchez-Pérez, I., Matallanas, D., León, J., Perona, R.,
and Crespo, P. Subcellular localization determines the protective effects of activated
ERK2 against distinct apoptogenic stimuli in myeloid leukemia cells. J Biol Chem.
279:32819-32823 (2004). PDF
o Bastida, M.F., Delgado, M.D., Wang, B., Fallon, J.F., Fernandez-Terán, M. and
Ros, M.A. Levels of Gli3 repressor correlate with Bmp4 expression and apoptosis
during limb development. Dev. Dynamics 231:148-160 (2004).
o Domínguez-Cáceres, M.A., García-Martínez, J.M., Calcabrini, A., González, L.,
González Porque, P., León, J. and Martín-Pérez, J. Prolactin induces c-Myc expression
and cell survival through activation of Src/Akt pathway in lymphoid cells. Oncogene
23:7378-7390 (2004).
o Gómez-Casares, M.T., Vaqué, J.P., Lemes, A., Molero, T., Delgado, M.D. and
León, J. c-myc expression in cell lines derived from chronic myeloid leucemia.
Haematologica. 89:241-243 (2004).
o Mauleon, I., Lombard, M.N., Muñoz-Alonso, M.J., Cañelles, M., and León, J.
Kinetics of myc-max-mad gene expression during hepatocyte proliferation in vivo:
differential regulation of mad family and stress-mediated induction of c-myc. Mol
Carcinogenesis. 39:85-90 (2004).
o Acosta, J.C., Richard, C., Delgado, M.D., Horita, M., Rizzo, M.G., FernándezLuna, J.L. and León, J. Amifostine impairs p53-mediated apoptosis of human myeloid
leukemia cells. Mol. Cancer Ther. 2: 893-900 (2003).
o Muñoz-Alonso, M. J., and León, J. G1 phase control and differentiation. In "G1
Phase Progression". J. Boonstra (ed.), Landes Bioscience (2003) pp 236-264.
o Wu, S., Cetinkaya, C., Munoz-Alonso. M.J., von der Lehr, N., Bahram, F.,
Beuger, V., Eilers, M. Leon, J. and Larsson, L.-G.. Myc represses differentiation-induced
p21Cip1 expression via Miz-1-dependent interaction with the p21 core promoter.
Oncogene 22: 351-360 (2003).
o Barradas, M., Gonos, E.S., Zebedee, Z., Kolettas, E., Petropoulou, C., Delgado,
M.D., León, J. Hara, E., and Serrano, M., Identification of a candidate tumor suppressor
genes specifically activated during Ras-induced senescence. Exp Cell Res. 273:127-137
(2002)
o Piedra, E., Delgado, M.D., Ros, M.A. and León, J. c-Myc overexpression
increases cell size and impairs cartilage differentiation during chick limb development
Cell Growth Diff 13: 185-193 (2002).
o W. Lutz, J. Leon and M. Eilers. Contributions of c-Myc to tumorigenesis.
Biochem. Biophys Acta- Reviews on Cancer.1602: 61-71 (2002).
o Pipaón, C., Gutierrez, P., Montero, P.C., Lorenzo, M., Eguiraun, A., De la
Fuente, J.A., Pandiella, A., León, J., and Ortiz, J.M. Mitogen-activated protein kinase
routes as targets in the action of diaza-anthracene compounds with potent growthinhibitory effect on cancer cells. Mol. Cancer Ther. 1: 811-819 (2002).
o Bolufer P, Lo Coco F, Grimwade D, Barragan E, Diverio D, Cassinat B,
Chomienne C, Gonzalez M, Colomer D, Gomez MT, Marugan I, Roman J, Delgado MD,
Garcia-Marco JA, Bornstein R, Vizmanos JL, Martinez B, Jansen J, Villegas A, de Blas JM,
Cabello P, Sanz MA. Variability in the levels of PML-RARa fusion transcripts detected by
the laboratories participating in an external quality control program using several
reverse transcription polymerase chain reaction protocols. Haematologica. 86:570-576
(2001).
o Klenova, E.M., Chernukhin, I., El-Kady, A., Lee, R.E., Pugacheva, E., Graham H.
Goodwin, G.H., Delgado, M.D., Filippova, G.N., León, J., Neiman, P., and Lobanenkov, V.
Functional CKII phosphorylation sites in the C-terminal region of the multivalent
multifunctional transcriptional factor CTCF. Mol. Cell. Biol. 21: 2221-2234 (2001).
o Rasko, J.E.J, Klenova, E.M., Leon, J., Filippova, G.M., Loukinov, D., Vatolin, S.,
Qi, C.F., Hu, Y.J., Ulmer, J, Ward, M.D., Mueller, L., Lee, R.E., Neiman, P.E., Morse H.C.,
Collins, S.J., and Lobanenkov, V.V. Cell growth inhibition by the multivalent
multifunctional transcriptional factor CTCF. Cancer Res. 61: 6002-6007 (2001)
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Contacto:
Dr. Javier León
Departamento de Biología Molecular
IBBTEC - Universidad de Cantabria
(+34) 942 201952
Fax 942 201945
leonj@unican.es