Fred Hutchinson Cancer Research Center

About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.

SR proteins: a conserved family of pre-mRNA splicing factors.

Abstract: We demonstrate that four different proteins from calf thymus are able to restore splicing in the same splicing-deficient extract using several different pre-mRNA substrates. These proteins are members of a conserved family of proteins recognized by a monoclonal antibody that binds to active sites of RNA polymerase II transcription. We purified this family of nuclear phosphoproteins to apparent homogeneity by two salt precipitations. The family, called SR proteins for their serine- and arginine-rich carboxy-terminal domains, consists of at least five different proteins with molecular masses of 20, 30, 40, 55, and 75 kD. Microsequencing revealed that they are related but not identical. In four of the family members a repeated protein sequence that encompasses an RNA recognition motif was observed. We discuss the potential role of this highly conserved, functionally related set of proteins in pre-mRNA splicing.

Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24

Abstract: Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer.

Regional and cellular gene expression changes in human Huntington's disease brain.

Abstract: Huntington's disease (HD) pathology is well understood at a histological level but a comprehensive molecular analysis of the effect of the disease in the human brain has not previously been available. To elucidate the molecular phenotype of HD on a genome-wide scale, we compared mRNA profiles from 44 human HD brains with those from 36 unaffected controls using microarray analysis. Four brain regions were analyzed: caudate nucleus, cerebellum, prefrontal association cortex [Brodmann's area 9 (BA9)] and motor cortex [Brodmann's area 4 (BA4)]. The greatest number and magnitude of differentially expressed mRNAs were detected in the caudate nucleus, followed by motor cortex, then cerebellum. Thus, the molecular phenotype of HD generally parallels established neuropathology. Surprisingly, no mRNA changes were detected in prefrontal association cortex, thereby revealing subtleties of pathology not previously disclosed by histological methods. To establish that the observed changes were not simply the result of cell loss, we examined mRNA levels in laser-capture microdissected neurons from Grade 1 HD caudate compared to control. These analyses confirmed changes in expression seen in tissue homogenates; we thus conclude that mRNA changes are not attributable to cell loss alone. These data from bona fide HD brains comprise an important reference for hypotheses related to HD and other neurodegenerative diseases.

Upstream open reading frames as regulators of mRNA translation.

Abstract: Continuing discoveries of new and surprising mechanisms of gene regulation suggest that our understanding of this complex and ubiquitous biological process remains incomplete. Emerging examples illustrate that many and perhaps all genes are regulated at multiple steps including transcription, posttranscriptional processing, nuclear export and localization, stability, and translation of mature mRNA molecules. Translation itself is regulated by a diverse collection of mechanisms that act not only at the initiation step but also during elongation and termination and even after termination. Among the various cis elements in mRNAs (43) that participate in regulating translation are AUG codons within transcript leaders (upstream AUGs [uAUGs]) and, in some cases, associated upstream open reading frames (uORFs). Based on a 1987 survey, less than 10% of eukaryotic mRNAs contain AUG codons within their transcript leader regions (often erroneously referred to as 5′ untranslated regions). However, uAUGs are conspicuously common in certain classes of genes, including two-thirds of oncogenes and many other genes involved in the control of cellular growth and differentiation (29, 31, 42). Despite the wealth of sequence data being generated by large-scale sequencing projects, extracting an up-to-date, comprehensive, and accurate estimate of the number of genes with uORFs is a formidable task. Only a minority of database entries are based on careful mRNA mapping data with annotations that identify the precise start of the transcript leader. Moreover, the use of alternative transcriptional start sites, alternative RNA processing, and alternative initiation codons complicates the determination of what exactly constitutes the transcript leader. Nonetheless, it is clear that uAUGs are not uncommon in genes with critical cellular roles, and identifying when and how they function is necessary if we are to achieve a comprehensive understanding of the interesting genes that contain these elements and of eukaryotic gene regulation in general. Some of the general principles by which uORFs participate in translational control are beginning to be understood. In this article, we first review these principles, which include the process of recognition of uORFs, regulation of reinitiation at downstream cistrons after translation of uORFs, and regulatory effects of peptides encoded by uORFs. We then illustrate how these principles are applied by reviewing several specific examples where the roles of uORFs in translational control have been well characterized.