CHUK, a new member of the helix-loop-helix and leucine zipper families of interacting proteins, contains a serine threonine kinase catalytic domain
CELLULAR & MOLECULAR BIOLOGY RESEARCH
Authors: Connelly, MA; Marcu, KB
Abstract
We have identified a new member of the helix-loop-helix (H-L-H) and leucine zipper gene families via a reverse transcriptase-polymerase chain reaction based strategy. This new gene, CHUK (conserved helix-loop-helix ubiquitous kinase). may represent the founding member of a new class of interacting chimeric proteins. The nucleotide sequence of a near full-length murine CHUK cDNA clone revealed an encoded polypeptide specifying: a carboxy-terminal H-L-H domain, an amino terminal serine-threonine kinase catalytic domain, and a leucine zipper-like amphipathic cy-helix juxtaposed in between the H-L-H and kinase domains. CHUK is highly conserved in evolution and ubiquitously expressed in diverse types of established cell lines, whereas it is differentially expressed in normal murine tissues. The structural features of the CHUK polypeptide suggest that its putative kinase activity may be targetted to H-L-H and/ or leucine zipper transcription factors. Alternatively, the dual amphipathic a helices may serve to control its intrinsic kinase activity by interactions with other cellular factors. CHUK may provide new insights into the regulated transmission of cytoplasmic signals to specific nuclear factors manifesting rapid alterations in patterns of cellular gene expression.
Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis
PHARMACOGENOMICS JOURNAL
Authors: Ferreiro-Iglesias, A.; Montes, A.; Perez-Pampin, E.; Canete, J. D.; Raya, E.; Magro-Checa, C.; Vasilopoulos, Y.; Sarafidou, T.; Caliz, R.; Ferrer, M. A.; Joven, B.; Carreira, P.; Balsa, A.; Pascual-Salcedo, D.; Blanco, F. J.; Moreno-Ramos, M. J.; Fernandez-Nebro, A.; Ordonez, M. C.; Alegre-Sancho, J. J.; Narvaez, J.; Navarro-Sarabia, F.; Moreira, V.; Valor, L.; Garcia-Portales, R.; Marquez, A.; Martin, J.; Gomez-Reino, J. J.; Gonzalez, A.
Abstract
Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B = 0.33, P = 0.006). This is the second independent replication of this biomarker (P = 9.08 x 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.