The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary proliferation

Peters, Gregory A.; Seachrist, Darcie D.; Keri, Ruth A.; Sen, Ganes C.

doi:10.1073/pnas.0900735106

Cited by 27 publications

(33 citation statements)

References 40 publications

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“…These data highlight a functional role for PACT, supporting the notion that it may be a key transcriptional regulator of endocrine hormone signaling and the concept that overexpression of PACT in cancer could promote tumorigenesis (24). This implication of PACT in endocrine signaling is consistent with its reported role in postnatal anterior pituitary proliferation (25). Our findings add to the repertoire of functions of PACT, which includes the regulation of retinoic-acid-inducible gene 1 expression as part of the antiviral response (26), and ear development and hearing (27).…”

Section: Discussionsupporting

confidence: 78%

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

Redfern

Colley

Beveridge

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. There is increasing evidence for important functional interactions between the miRNA and nuclear receptor (NR) signaling networks, with recent data showing that estrogen, acting through the estrogen receptor, can modulate initial aspects of nuclear miRNA processing. Here, we show that the cytoplasmic RISC proteins PACT, TRBP, and Dicer are steroid receptor RNA activator (SRA) binding NR coregulators that target steroid-responsive promoters and regulate NR activity and downstream gene expression. Furthermore, each of the RISC proteins, together with Argonaute 2, associates with SRA and specific pre-microRNAs in both the nucleus and cytoplasm, providing evidence for links between NR-mediated transcription and some of the factors involved in miRNA processing.noncoding RNA | androgen action | prostate cancer M icroRNAs (miRNAs) are 22-nt noncoding RNAs that regulate gene expression by associating with the multiprotein RNA-induced silencing complex (RISC) and guiding RISC to silence specific mRNA species by mRNA degradation or translational inhibition (1). miRNAs are derived from large primary RNA transcripts, which are processed in the nucleus by Drosha/ Pasha into ∼70-nt precursor (pre-miRNA) duplexes. These duplexes are exported to the cytoplasm, and their conversion to mature 22-nt miRNAs is mediated by a transactivation response (TAR) RNA binding protein (TRBP)-Dicer complex (1), which provides a platform for RISC assembly and aids recruitment of Argonaute 2 (Ago2), the catalytic enzyme of RISC required for miRNA processing (2, 3). Protein kinase RNA (PKR) activator (PACT) is also integral to the RISC complex and associates with Dicer (4). TRBP and PACT are critical for efficient miRNA processing, because their depletion results in decreased mature miRNA levels and target gene silencing (2, 4, 5).Ligand-activated signaling by nuclear receptors (NRs) plays a key role in the promotion of human tumorigenesis. NR coregulators are a group of >300 molecules that act to fine tune ligand-induced gene transcription by acting as either coactivators [e.g., steroid receptor coactivator-1 (SRC-1)] or corepressors [e.g., nuclear receptor corepressor1 (NCoR1)] (6). One of the NR coregulators, steroid receptor RNA activator (SRA), is unique, because its RNA transcript functions to coactivate NR activity (7-9).Several links between miRNA pathways and NR action have been reported. miRNAs can regulate NR signaling at different levels, including targeting NRs [e.g., estrogen receptor-α (ERα)] (10, 11) or NR coregulator transcripts (e.g., amplified in breast cancer 1) (12). Conversely, NRs regulate an array of miRNAs in endocrine tissues (13). For example, ERα can regulate miRNA-21 expression at the transcriptional level (14) and the...

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Section: Discussionsupporting

confidence: 78%

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

Redfern

Colley

Beveridge

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast to mice in which the Eif2ak2 gene has been disrupted ( Eif2ak2 tm1Cwe/tm1Cwe ), which had no discernable developmental phenotype [24], Prkra tm1Gsc/tm1Gsc mice showed defects in ear and craniofacial development, growth and fertility [25]. Further investigation revealed that Prkra tm1Gsc/tm1Gsc mice developed hypoplastic anterior pituitaries resulting from reduced cell proliferation in this tissue [26]. As the anterior pituitary contains cells which secrete hormones required for growth and sexual development, this likely accounts for some of the developmental anomalies observed in the mouse [26].…”

Section: Introductionmentioning

confidence: 96%

Missense Mutation in the Second RNA Binding Domain Reveals a Role for Prkra (PACT/RAX) during Skull Development

et al. 2011

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Random chemical mutagenesis of the mouse genome can causally connect genes to specific phenotypes. Using this approach, reduced pinna (rep) or microtia, a defect in ear development, was mapped to a small region of mouse chromosome 2. Sequencing of this region established co-segregation of the phenotype (rep) with a mutation in the Prkra gene, which encodes the protein PACT/RAX. Mice homozygous for the mutant Prkra allele had defects not only in ear development but also growth, craniofacial development and ovarian structure. The rep mutation was identified as a missense mutation (Serine 130 to Proline) that did not affect mRNA expression, however the steady state level of RAX protein was significantly lower in the brains of rep mice. The mutant protein, while normal in most biochemical functions, was unable to bind dsRNA. In addition, rep mice displayed altered morphology of the skull that was consistent with a targeted deletion of Prkra showing a contribution of the gene to craniofacial development. These observations identified a specific mutation that reduces steady-state levels of RAX protein and disrupts the dsRNA binding function of the protein, demonstrating the importance of the Prkra gene in various aspects of mouse development.

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“…Substitution of both residues with the phosphoserine mimetic, aspartic acid, produces a mutant PACT which will induce PKR activation and apoptosis, even in unstressed cells (Peters et al, 2006). While in stressed cells, mutant PACT activates PKR more effectively and has a tighter association with PKR (Peters et al, 2009). Phosphorylation at serine 246 and 287 is essential for PACT-PACT and PACT-PKR interaction.…”

Section: Pact/rax and Pkrmentioning

confidence: 99%

“…In addition, Pact −/− mice have smaller body size and fertility defects caused by defective pituitary functions. Pact −/− mice exhibit anterior pituitary lobe (AL) hypoplasia, which develops postnatally, when the second phase of pituitary expansion occurs (Peters et al, 2009). In another knockout mouse model, deletion of the entire Rax gene results in no mice homozygous for the mutant allele.…”

Section: Pact/rax and Developmentmentioning

confidence: 99%

dsRNA binding protein PACT/RAX in gene silencing, development and diseases

2014

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PACT (Protein kinase, interferon-inducible double stranded RNA dependent activator) and its murine ortholog RAX (PKR-associated protein X) were originally identified as a protein activator for the dsRNA-dependent, interferon-inducible protein kinase (PKR). Endogenous PACT/RAX activates PKR in response to diverse stress signals such as serum starvation, and peroxide or arsenite treatment. PACT/RAX heterodimerized with PKR and activated it with its third motif in the absence of dsRNA. The activation of PKR leads to enhanced eIF2α phosphorylation followed by apoptosis or inhibition of growth. Besides the role of activating PKR, PACT is associated with a ~500 kDa complex that contains Dicer, hAgo2, and TRBP (TAR RNA binding protein) and it associates with Dicer to facilitate the production of small interfering RNA. PACT/RAX plays an important role in diverse physiological and pathological processes. Pact−/− mice exhibit notable developmental abnormalities including microtia, with craniofacial ear, and hearing defects. Pact−/− mice had smaller body sizes and fertility defects, both of which were caused by defective pituitary functions. It was found that dRAX disrupted fly embryos homozygous, displayed highly abnormal commissural axon structure of the central nervous system, and 70% of the flies homozygous for the mutant allele died prior to adulthood. Using high density SNP genotyping arrays, it was found that a mutation in PRKRA (the PACT/RAX gene) is the causative genetic mutation in DYT16, a novel autosomal recessive dystonia-parkinsonism syndrome in Brazilian patients.

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The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary proliferation

Cited by 27 publications

References 40 publications

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators

Missense Mutation in the Second RNA Binding Domain Reveals a Role for Prkra (PACT/RAX) during Skull Development

dsRNA binding protein PACT/RAX in gene silencing, development and diseases

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