Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs)

Persengiev, Stephan P.; Zhu, Xiaochun; Green, Michael R.

doi:10.1261/rna5160904

Cited by 465 publications

(320 citation statements)

References 21 publications

(33 reference statements)

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“…For hsRpb7 four longer than normal 27mer siRNAs (R7L1-4) were tested because longer siRNAs are more potent (Kim et al, 2005) and thus can be used at concentrations (20 nmol/L) low enough to reduce potential off-target effects (Persengiev et al, 2004). Three of the above siRNAs (R7L1, R7L3 and R7L4) had strong silencing activity at 20 nmol/L (Fig.…”

Section: Identification Of Effective Hsrpb4/7 Sirnasmentioning

confidence: 99%

The RNA Pol II sub-complex hsRpb4/7 is required for viability of multiple human cell lines

Zhao¹,

Li²,

Ng³

et al. 2012

Protein Cell

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The evolutionarily conserved RNA Polymerase II Rpb4/7 sub-complex has been thoroughly studied in yeast and impacts gene expression at multiple levels including transcription, mRNA processing and decay. In addition Rpb4/7 exerts differential effects on gene expression in yeast and Rpb4 is not obligatory for yeast (S. cerevisiae) survival. Specialised roles for human (hs) Rpb4/7 have not been extensively described and we have probed this question by depleting hsRpb4/7 in established human cell lines using RNA interference. We find that Rpb4/7 protein levels are inter-dependent and accordingly, the functional effects of depleting either protein are co-incident. hsRpb4/7 exhibits gene-specific effects and cells initially remain viable upon hsRpb4/7 depletion. However prolonged hsRpb4/7 depletion is cytotoxic in the range of cell lines tested. Protracted cell death occurs by an unknown mechanism and in some cases is accompanied by a pronounced elongated cell morphology. In conclusion we provide evidence for a gene-specific role of hsRpb4/7 in human cell viability.

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Section: Identification Of Effective Hsrpb4/7 Sirnasmentioning

confidence: 99%

The RNA Pol II sub-complex hsRpb4/7 is required for viability of multiple human cell lines

Zhao¹,

Li²,

Ng³

et al. 2012

Protein Cell

View full text Add to dashboard Cite

show abstract

“…Moreover, their results suggested that the most effective siRNA overhangs have a UU or TT sequence. Since then, most of the reported siRNA sequences have been 21 bp in length (although there have also been reports of effective 23 bp [123][124][125][126][127] The action of siRNA depends on many cellular proteins; therefore, various organisms may respond to siRNA in slightly different manners. As cellular antiviral systems are intertwined with the siRNA system, the innate immune system (specifically the interferon response and the NF-kB-modulated inflammation response through Toll-like receptors) may be stimulated by siRNA.…”

Section: Rnai and Functional Genomicsmentioning

confidence: 99%

siRNA-based approaches in cancer therapy

2006

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The availability of the human genome sequence has revolutionized the strategy of employing nucleic acids with sequences complementary to specific target genes to improve drug discovery and target validation. Development of sequence-specific DNA or RNA analogs that can block the activity of selected single-stranded genetic sequences offers the possibility of rational design with high specificity, lacking in many current drug treatments for various diseases including cancer, at relatively inexpensive costs. Antisense technology is one such example that has shown promising results and boasts of yielding the only approved drug to date in the genomics field. However, in vivo delivery issues have yet to be completely overcome for widespread clinical applications. In contrast to antisense oligonucleotides, the mechanism of silencing an endogenous gene by the introduction of a homologous double-stranded RNA (dsRNA), transgene or virus is called post-transcriptional gene silencing (PTGS) or RNA interference. PTGS is a natural mechanism whereby metazoan cells suppress expansion of genes when they come across dsRNA molecules with the same sequence. Short interfering RNA is currently the fastest growing sector of this antigene field for target validation and therapeutic applications. Although, in theory, the development of genomics-based agents to inhibit gene expression is simple and straightforward, the fundamental concern relies upon the capacity of the oligonucleotide to gain access to the target RNA. This paper summarizes the advances in the last decade in the field of PTGS using RNA interference approaches and provides relevant comparisons with other oligonucleotide-based approaches with a specific focus on oncology applications. Cancer Gene Therapy (2006) Genomic-based strategiesThe American Cancer Society estimates that, in 2005, a total of 1 372 910 new cancer cases and 570 280 deaths are expected in the United States. 1 These morbid statistics demonstrate the necessity of newer therapeutic modalities for achieving successful cancer treatment and cure. Downregulation of genes that contribute to cancer progression has been the goal of targeted genomics-based strategies, with the expectation that such an approach may lead to selective and specific inhibition of tumor growth with minimal untoward side effects on normal cells. Identification of target genes involved in neoplastic transformation and tumor progression has triggered the idea that nucleotide sequences of cancer-relevant genes could lead to the development of tailored anticancer agents that lack many of the toxic side effects of traditional cytotoxic drugs. This has led to a recent acceleration in the development and optimization of genomic-based strategies for cancer therapy. This idea dates back to the 1960s when RNA sequences were shown to serve as endogenous inhibitors of gene expression in procaryotes. The antigene approaches include the following:(1) Ribozymes: 2,3 These were discovered in the 1970s, and the elucidation of the transactivating hammerh...

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“…These effects are strongly correlated to protein concentrations in the cells. Upper doses are not recommanded as non-specific effects on genes regulation has already been described as dependent upon siRNA concentrations [145]. High doses of siRNA administration affect multiple signaling and transcription pathways in addition to a marked influence on protein kinase response and activation of toll-like receptors [146][147][148].…”

Section: Mmp-12 Silencingmentioning

confidence: 99%

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

Garbacki¹,

Valentin²,

Piette³

et al. 2009

Pulmonary Pharmacology & Therapeutics

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Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs)

Cited by 465 publications

References 21 publications

The RNA Pol II sub-complex hsRpb4/7 is required for viability of multiple human cell lines

The RNA Pol II sub-complex hsRpb4/7 is required for viability of multiple human cell lines

siRNA-based approaches in cancer therapy

Matrix metalloproteinase 12 silencing: A therapeutic approach to treat pathological lung tissue remodeling?

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