SAFB1's multiple functions in biological control—lots still to be done!

Garee, Jason P.; Oesterreich, Steffi

doi:10.1002/jcb.22420

Cited by 37 publications

(52 citation statements)

References 56 publications

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“…Q80-CFP aggregates did not alter the localization or sequester endogenous hnRNPA1 or SAFB1 (Fig. 2, A and B) (34). This is particularly notable as hnRNPA1 has a similar domain structure to TDP-43, with two RNA-binding motifs and a C-terminal glycine-rich region (35).…”

Section: Polyglutamine Aggregates Sequester Tdp-43 and Deplete It Fromentioning

confidence: 82%

Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43

Fuentealba

Udan

Bell

et al. 2010

Journal of Biological Chemistry

146

128

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The identification of pathologic TDP-43 aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, followed by the discovery of dominantly inherited point mutations in TDP-43 in familial ALS, have been critical insights into the mechanism of these untreatable neurodegenerative diseases. However, the biochemical basis of TDP-43 aggregation and the mechanism of how mutations in TDP-43 lead to disease remain enigmatic. In efforts to understand how TDP-43 alters its cellular localization in response to proteotoxic stress, we found that TDP-43 is sequestered into polyglutamine aggregates. Furthermore, we found that binding to polyglutamine aggregates requires a previously uncharacterized glutamine/asparagine (Q/N)-rich region in the C-terminal domain of TDP-43. Sequestration into polyglutamine aggregates causes TDP-43 to be cleared from the nucleus and become detergent-insoluble. Finally, we observed that sequestration into polyglutamine aggregates led to loss of TDP-43-mediated splicing in the nucleus and that polyglutamine toxicity could be partially rescued by increasing expression of TDP-43. These data indicate pathologic sequestration into polyglutamine aggregates, and loss of nuclear TDP-43 function may play an unexpected role in polyglutamine disease pathogenesis. Furthermore, as Q/N domains have a strong tendency to self-aggregate and in some cases can function as prions, the identification of a Q/N domain in TDP-43 has important implications for the mechanism of pathologic aggregation of TDP-43 in ALS and other neurodegenerative diseases.Abnormal protein aggregation is a hallmark of most inherited and acquired neurodegenerative diseases. Recently, TDP-43 was identified as a component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) 4 (1). The subsequent finding of mutations in TDP-43 in cases of inherited ALS indicates that TDP-43 can be directly involved in the pathogenesis of at least the familial forms of this disease (2-6). It is notable that although aggregates of a particular protein are initially associated with a specific clinical and pathologic syndrome, they are often observed in multiple other neurodegenerative disorders. For example, although cytoplasmic inclusions of TDP-43 were initially described in ALS and FTLD, they have also been observed in Alzheimer disease, diffuse Lewy body disease, dementia pugilistica, Huntington disease, and even inclusion body myopathies (7-11). Whether TDP-43 translocation to the cytosol and aggregation plays a direct role in the pathogenesis of these disorders, or instead is part of a more general cellular stress response, remains to be elucidated (12).Polyglutamine diseases are a family of neurodegenerative disorders caused by expansion of a CAG trinucleotide repeat in the coding regions of certain genes. Examples include Huntington disease, X-linked spinal-bulbar muscular atrophy, and several of the spinocerebellar ataxias (13-15). Expanded polyglutamine proteins have a ...

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Section: Polyglutamine Aggregates Sequester Tdp-43 and Deplete It Fromentioning

confidence: 82%

Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43

Fuentealba

Udan

Bell

et al. 2010

Journal of Biological Chemistry

146

128

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“…One of the first reports described binding of SAFB to the promoter of the heat-shock protein 27 gene and consequent inhibition of expression [9]. Subsequently, investigations carried out by the Oesterreich group have related to repressive effects of SAFB on oestrogen receptor signalling (reviewed in Oesterreich [75] and Garee and Oesterreich [76]). As with many other RBPs [11,[77][78][79][80], overexpression of SAFB proteins produces generalised inhibition of RNA synthesis and eventual apoptosis [11,13].…”

Section: Transcriptionmentioning

confidence: 99%

“…The Oesterreich group has carried out the most extensive investigation of SAFB functions in vivo (reviewed by Garee and Oesterreich [76] and Hong et al [106]). Ivanova et al [107] generated SAFB1 −/− mutant mice and found that loss of SAFB1 was associated with pre-and post-natal lethality.…”

Section: Safb Function In Vivo and Possible Roles In Human Diseasementioning

confidence: 99%

The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

Norman

Rivers

Lee

et al. 2016

Biochemical Journal

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RNA-binding proteins play a central role in cellular metabolism by orchestrating the complex interactions of coding, structural and regulatory RNA species. The SAFB (scaffold attachment factor B) proteins (SAFB1, SAFB2 and SAFB-like transcriptional modulator, SLTM), which are highly conserved evolutionarily, were first identified on the basis of their ability to bind scaffold attachment region DNA elements, but attention has subsequently shifted to their RNA-binding and protein-protein interactions. Initial studies identified the involvement of these proteins in the cellular stress response and other aspects of gene regulation. More recently, the multifunctional capabilities of SAFB proteins have shown that they play crucial roles in DNA repair, processing of mRNA and regulatory RNA, as well as in interaction with chromatin-modifying complexes. With the advent of new techniques for identifying RNA-binding sites, enumeration of individual RNA targets has now begun. This review aims to summarise what is currently known about the functions of SAFB proteins.

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“…As a nuclear matrix protein with multiple domains, SAFB serves as a transcription factor that regulates the expression of target genes and the activity of many signaling pathways that play important roles in various cellular processes (7,8,26). Interestingly, we discovered that the downregulation of SAFB was correlated with the activation of the NF-kB signaling pathway.…”

Section: Discussionmentioning

confidence: 68%

Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer

Jiao

Yang

et al. 2017

Clinical Cancer Research

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Purpose: To investigate the role and the underlying mechanism of scaffold attachment factor B (SAFB) in the progression of colorectal cancer (CRC).Experimental Design: SAFB expression was analyzed in the Cancer Outlier Profile Analysis of Oncomine and in 175 paraffinembedded archived CRC tissues. Gene Ontology analyses were performed to explore the mechanism of SAFB in CRC progression. Western blot, RT-PCR, luciferase assay, and chromatin immunoprecipitation (ChIP) were used to detect the regulation of transforming growth factor-b-activated kinase 1 (TAK1) and NF-kB signaling by SAFB. The role of SAFB in invasion, metastasis, and angiogenesis was investigated using in vitro and in vivo assays. The relationship between SAFB and TAK1 was analyzed in CRC tissues.Results: SAFB was downregulated in CRC tissues, and low expression of SAFB was significantly associated with an aggressive phenotype and poorer survival of CRC patients. The downregulation of SAFB activated NF-kB signaling by targeting the TAK1 promoter. Ectopic expression of SAFB inhibited the development of aggressive features and metastasis of CRC cells both in vitro and in vivo. The overexpression of TAK1 could rescue the aggressive features in SAFB-overexpressed cells. Furthermore, the expression of SAFB in CRC tissues was negatively correlated with the expression of TAK1-and NF-kBrelated genes.Conclusions: Our results show that SAFB regulated the activity of NF-kB signaling in CRC by targeting TAK1. This novel mechanism provides a comprehensive understanding of both SAFB and the NF-kB signaling pathway in the progression of CRC and indicates that the SAFB-TAK1-NF-kB axis is a potential target for early therapeutic intervention in CRC progression. Clin Cancer Res; 23(22); 7108-18. Ó2017 AACR.

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SAFB1's multiple functions in biological control—lots still to be done!

Cited by 37 publications

References 56 publications

Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43

Interaction with Polyglutamine Aggregates Reveals a Q/N-rich Domain in TDP-43

The increasing diversity of functions attributed to the SAFB family of RNA-/DNA-binding proteins

Downregulation of SAFB Sustains the NF-κB Pathway by Targeting TAK1 during the Progression of Colorectal Cancer

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