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Proteasome beta subunit pharmacogenomics: gene resequencing and functional genomics.

ABSTRACT: The proteasome is a multisubunit cellular organelle that functions as a nonlysosomal threonine protease. Proteasomes play a critical role in the degradation of proteins, regulating a variety of cellular processes, and they are also the target for antineoplastic proteasome inhibitors. Genetic variation in proteasome subunits could influence both proteasome function and response to drug therapy.We resequenced genes encoding the three active proteasome beta subunits using 240 DNA samples from four ethnic groups and the beta 5 subunit gene in 79 DNA samples from multiple myeloma patients who had been treated with the proteasome inhibitor bortezomib. Resequencing was followed by functional studies of polymorphisms identified in the coding region and 3'-flanking region (3'-FR) of PSMB5, the gene encoding the target for clinically useful proteasome inhibitors.Resequencing of 240 DNA samples identified a series of novel ethnic-specific polymorphisms that are not represented in public databases. The PSMB5 3'-FR 1042 G allele significantly increased transcription during reporter gene studies, observations confirmed by genotype-phenotype correlations between single nucleotide polymorphisms (SNP) in PSMB5 and mRNA expression in the 240 lymphoblastoid cell lines from which the resequenced DNA was obtained. Studies with patient DNA samples identified additional novel PSMB5 polymorphisms, including a SNP and an insertion in the 3'-FR. Reporter-gene studies indicated that these two novel polymorphisms might decrease transcription.These results show that nonsynonymous coding SNPs in the PSMB5 gene did not show significant effects on proteasome activity, but SNPs did influence transcription. Future studies might focus on regulatory region polymorphisms.

SUBMITTER: Wang L

PROVIDER: S-EPMC2778274 | biostudies-literature | 2008 Jun

REPOSITORIES: biostudies-literature

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Proteasome beta subunit pharmacogenomics: gene resequencing and functional genomics.

Wang Liewei L Kumar Shaji S Fridley Brooke L BL Kalari Krishna R KR Moon Irene I Pelleymounter Linda L LL Hildebrandt Michelle A T MA Batzler Anthony A Eckloff Bruce W BW Wieben Eric D ED Greipp Philip R PR

Clinical cancer research : an official journal of the American Association for Cancer Research 20080601 11

<h4>Purpose</h4>The proteasome is a multisubunit cellular organelle that functions as a nonlysosomal threonine protease. Proteasomes play a critical role in the degradation of proteins, regulating a variety of cellular processes, and they are also the target for antineoplastic proteasome inhibitors. Genetic variation in proteasome subunits could influence both proteasome function and response to drug therapy.<h4>Experimental design</h4>We resequenced genes encoding the three active proteasome be ...[more]

PMID: 18519783

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Proteasome beta subunit pharmacogenomics: gene resequencing and functional genomics.

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Proteasome beta subunit pharmacogenomics: gene resequencing and functional genomics.

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