title: High p27 protein levels in chronic lymphocytic leukemia are associated to low Myc and Skp2 expression, confer resistance to apoptosis and antagonize Myc effects on cell cycle.
abstract: Myc (c-Myc) counteracts p27 effects, and low p27 usually correlates with high Myc expression in human cancer. However there is no information on the co-expression of both genes in chronic lymphocytic leukemia (CLL). We found a lack of correlation between RNA and protein levels of p27 and Myc in CLL cells, so we determined the protein levels by immunoblot in 107 cases of CLL. We observed a high p27 protein expression in CLL compared to normal B cells. Ectopic p27 expression in a CLL-derived cell line resulted in cell death resistance. Surprisingly, Myc expression was very low or undetectable in most CLL cases analyzed, with a clear correlation between high p27 and low Myc protein levels. This was associated with low Skp2 expression, which is consistent with the Skp2 role in p27 degradation and with SKP2 being a Myc target gene. High Myc expression did not correlate with leukemia progression, despite that cell cycle-related Myc target genes were upregulated. However, biochemical analysis showed that the high p27 levels inhibited cyclin-Cdk complexes even in Myc expressing CLL cells. Our data suggest that the combination of high p27 and low Myc is a marker of CLL cells which is mediated by Skp2.
authors: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-Sodercan, and Dpt. of. Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors: Juan M
authors: JM
authors: Caraballo
authors: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-Sodercan, and Dpt. of. Biología Molecular, Universidad de Cantabria, Santander, Spain. Present address: Edinburgh Cancer Research UK Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK.
authors: Juan C
authors: JC
authors: Acosta
authors: Hospital de Laredo, Laredo, Santander, Spain.
authors: Miguel A
authors: MA
authors: Cortés
authors: Servicio de Hematologia, Hospital Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
authors: Marta
authors: M
authors: Albajar
authors: Servicio de Hematología, Hospital Dr. Negrin, Las Palmas, Spain.
authors: M Teresa
authors: MT
authors: Gómez-Casares
authors: Servicio de Hematologia, Hospital Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
authors: Ana
authors: A
authors: Batlle-López
authors: Servicio de Hematologia, Hospital Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
authors: M Angeles
authors: MA
authors: Cuadrado
authors: Servicio de Anatomía Patológica, Hospital Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
authors: Arantza
authors: A
authors: Onaindia
authors: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-Sodercan, and Dpt. of. Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors: Gabriel
authors: G
authors: Bretones
authors: Group of Epidemiology and Computational Biology, Universidad de Cantabria-IDIVAL, Santander, Spain and CIBER Epidemiología y Salud Pública (CIBERESP), Spain.
authors: Javier
authors: J
authors: Llorca
authors: Servicio de Anatomía Patológica, Hospital Marqués de Valdecilla and Instituto de Investigación Marqués de Valdecilla (IDIVAL), Santander, Spain.
authors: Miguel A
authors: MA
authors: Piris
authors: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Barcelona, Spain.
authors: Dolors
authors: D
authors: Colomer
authors: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), CSIC-Universidad de Cantabria-Sodercan, and Dpt. of. Biología Molecular, Universidad de Cantabria, Santander, Spain.
authors: Javier
authors: J
authors: León
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015151:Immunoblotting; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D016213:Cyclins; D020598:Proto-Oncogene Proteins c-myb; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27