Involvement of three glutamine tracts in human androgen receptor transactivation

Harada, Naoki; Mitani, Takahiko; Higashimura, Yasuki; Yamaji, Ryoichi; Okamoto, Ken‐ichi; Nakano, Yoshihisa; Inui, Hiroshi

doi:10.1016/j.jsbmb.2009.10.003

Cited by 12 publications

(11 citation statements)

References 38 publications

(41 reference statements)

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“…A similar overrepresentation was found in the interactomes of non-prionic proteins containing polyQ stretches that have a physiological function as the wild-type form (e.g. Harada et al, 2010), but acquire dysfunctional properties when genetic mutations increase their length above a critical threshold where they assume a pathogenic form that causes inherited disorders such as Huntington’s disease (Orr and Zoghbi, 2007). …”

Section: Introductionmentioning

confidence: 58%

Essential Role of Coiled Coils for Aggregation and Activity of Q/N-Rich Prions and PolyQ Proteins

Fiumara

Fioriti

Kandel

et al. 2010

Cell

229

327

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SUMMARY The functional switch of glutamine/asparagine (Q/N)-rich prions and the neurotoxicity of polyQ-expanded proteins involve complex aggregation-prone structural transitions, commonly presumed to be forming β-sheets. By analyzing sequences of interaction partners of these proteins, we discovered a recurrent presence of coiled-coil domains both in the partners and in segments that flank or overlap Q/N-rich and polyQ domains. Since coiled-coils can mediate protein interactions and multimerization, we studied their possible involvement in Q/N-rich and polyQ aggregations. Using circular dichroism and chemical cross-linking, we found that Q/N-rich and polyQ peptides form α-helical coiled-coils in vitro and assemble into multimers. Using structure-guided mutagenesis, we found that coiled-coil domains modulate in vivo properties of two Q/N-rich prions and polyQ-expanded huntingtin. Mutations that disrupt coiled-coils impair aggregation and activity, whereas mutations that enhance coiled-coil propensity promote aggregation. These findings support a coiled-coil model for the functional switch of Q/N-rich prions and for the pathogenesis of polyQ-expansion diseases.

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Section: Introductionmentioning

confidence: 58%

Essential Role of Coiled Coils for Aggregation and Activity of Q/N-Rich Prions and PolyQ Proteins

Fiumara

Fioriti

Kandel

et al. 2010

Cell

229

327

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“…As alterations in the number of trinucleotide repeats do not cause frameshifts in coding sequences, variation in these regions both between and within species is probably much better tolerated than other types of indels. Longer CAG repeats with little interruption by the alternative glutamine encoding codon CAA, are more likely to be associated with higher allele diversity (Figure 3) [11,35-39]. Polymerase slippage, unequal crossing-over during replication, and repair associated mechanisms, are the most likely explanations for this increased genetic diversity [4,40,41].…”

Section: Discussionmentioning

confidence: 99%

“…The absence of polymorphic variation in the poly-Q tract of the bovine androgen receptor (AR), a co-activator for androgen dependent gene transcription, is interesting in view of the links between poly-Q variation in the human protein and androgen-dependent diseases, many of which influence reproductive success [53,54]. As the AR gene is carried on the X chromosome some of these diseases result in somatic mosaicism [35]. The long history of cattle domestication involving intensive sire-based selection, primarily focussed on growth and reproductive traits, may have selected against variation in the AR gene in cattle.…”

Section: Discussionmentioning

confidence: 99%

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

et al. 2010

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BackgroundAbout forty human diseases are caused by repeat instability mutations. A distinct subset of these diseases is the result of extreme expansions of polymorphic trinucleotide repeats; typically CAG repeats encoding poly-glutamine (poly-Q) tracts in proteins. Polymorphic repeat length variation is also apparent in human poly-Q encoding genes from normal individuals. As these coding sequence repeats are subject to selection in mammals, it has been suggested that normal variations in some of these typically highly conserved genes are implicated in morphological differences between species and phenotypic variations within species. At present, poly-Q encoding genes in non-human mammalian species are poorly documented, as are their functions and propensities for polymorphic variation.ResultsThe current investigation identified 178 bovine poly-Q encoding genes (Q ≥ 5) and within this group, 26 genes with orthologs in both human and mouse that did not contain poly-Q repeats. The bovine poly-Q encoding genes typically had ubiquitous expression patterns although there was bias towards expression in epithelia, brain and testes. They were also characterised by unusually large sizes. Analysis of gene ontology terms revealed that the encoded proteins were strongly enriched for functions associated with transcriptional regulation and many contributed to physical interaction networks in the nucleus where they presumably act cooperatively in transcriptional regulatory complexes. In addition, the coding sequence CAG repeats in some bovine genes impacted mRNA splicing thereby generating unusual transcriptional diversity, which in at least one instance was tissue-specific. The poly-Q encoding genes were prioritised using multiple criteria for their likelihood of being polymorphic and then the highest ranking group was experimentally tested for polymorphic variation within a cattle diversity panel. Extensive and meiotically stable variation was identified.ConclusionsTranscriptional diversity can potentially be generated in poly-Q encoding genes by the impact of CAG repeat tracts on mRNA alternative splicing. This effect, combined with the physical interactions of the encoded proteins in large transcriptional regulatory complexes suggests that polymorphic variations of proteins in these complexes have strong potential to affect phenotype.

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“…A decrease in the length of Q-repeats enhances transactivation of AR and has been correlated with the increased risk of prostate cancer [37,38]. However, the correlation of the length of the Q-repeats and risk of cancer is controversial in female breast cancer and is thus not a prognostic marker in breast cancer [14,39,40] [41] [42].…”

Section: Androgen Receptor Structurementioning

confidence: 99%

The role of androgen receptor in breast cancer

Iacopetta

Rechoum

Fuqua

2012

Drug Discovery Today: Disease Mechanisms

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The androgen receptor (AR) is a proven clinical target in prostate cancer. Recent research indicates that it is an emerging hormonal target in breast cancer as well, with potential clinical benefit in both estrogen receptor(ER) positive and negative tumors. Compared to the ER, AR contains unique functional domains with relevance to its altered role in human breast cancer. The majority of ER-positive tumors express AR, and a significant percentage of ER-negative tumors might benefit from combined targeting of AR and the ErbB2/HER2 oncogene. Signaling downstream of AR might also affect many clinically important pathways which are also emerging clinical targets in breast cancer. AR expression might also play a role during tumor progression to metastatic disease. The role of AR as a new important biomarker in breast cancer will be reviewed herein.

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Involvement of three glutamine tracts in human androgen receptor transactivation

Cited by 12 publications

References 38 publications

Essential Role of Coiled Coils for Aggregation and Activity of Q/N-Rich Prions and PolyQ Proteins

Essential Role of Coiled Coils for Aggregation and Activity of Q/N-Rich Prions and PolyQ Proteins

Bovine proteins containing poly-glutamine repeats are often polymorphic and enriched for components of transcriptional regulatory complexes

The role of androgen receptor in breast cancer

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