The many roles of the conserved eukaryotic Paf1 complex in regulating transcription, histone modifications, and disease states

Tomson, Brett N.; Arndt, Karen M.

doi:10.1016/j.bbagrm.2012.08.011

Cited by 127 publications

(173 citation statements)

References 177 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…The fact that Ctr9-dependent expression of genes is involved in actin organization is consistent with a recent report that a PAF1-ERK5-ERα complex plays a role in actin reorganization via regulation of a transcriptional program of ERα in breast cancer (Madak-Erdogan et al 2014). PAFc has been previously shown to facilitate transcription elongation and transcription-coupled histone modifications (Tomson and Arndt 2013), including H2Bub1, which is required for ERα-regulated gene transcription (Prenzel et al 2011). Consistent with these reports, we demonstrated that Ctr9 promotes E2-stimulated transcription initiation by stimulating recruitment of ERα and RNAPII to target promoters and promoting downstream H3K27ac.…”

Section: Discussionsupporting

confidence: 79%

“…Finally, to explain the unique functional role of Ctr9 in ERα + breast cancer cells, we postulate that Ctr9 has novel interacting partners in this cellular context. Importantly, Ctr9 protein contains tetratrico peptide repeat (TPR) motifs that are important for protein-protein interaction (Chaudhary et al 2007;Tomson and Arndt 2013), and germline mutations in the TPR domain of Ctr9 predispose to Wilms tumor (Hanks et al 2014). Future proteomic studies of Ctr9-interacting proteins in MCF7 cells could provide insight into the mechanisms by which Ctr9 drives ERα + breast carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…6F). Because Ctr9 plays well-established roles in controlling transcription elongation and transcription-coupled histone modifications (Crisucci and Arndt 2011;Tomson and Arndt 2013), we examined the effects of Ctr9 knockdown on transcriptional elongation by RNA-PII and the coupled incorporation of H2Bub1 in ERα + breast cancer cells. Interestingly, Western blot analyses of the whole-cell lysates of MCF7-tet-on-shCtr9 cells revealed that E2 treatment substantially increased bulk levels of RNAPII pSer2 and H2Bub1, while Ctr9 knockdown decreased E2-induced RNAPII pSer2 as well as basal and E2-induced H2Bub1 (Fig.…”

Section: Ctr9 Regulates Estrogen-stimulated Transcription By Controllmentioning

confidence: 99%

“…PAFc plays a regulatory role during transcriptional initiation, elongation, and termination (Jaehning 2010; Kim et al 2010;Crisucci and Arndt 2011). PAFc has been well characterized for its role in controlling transcription-coupled histone modifications such as histone H2B monoubiquitination (H2Bub1), H3K4 trimethylation (H3K4me3), and H3K36me3 via interacting with the respective histone-modifying enzymes (Tomson and Arndt 2013). PAFc is evolutionarily conserved from yeast to Drosophila and humans; however, the hPAFc differs from yeast PAFc in one subunit: Ski8 (also known as WDR61) in humans and Rtf1 in yeast.…”

mentioning

confidence: 99%

See 3 more Smart Citations

Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Zeng

2015

Genes Dev.

View full text Add to dashboard Cite

The human RNA polymerase II (RNAPII)-associated factor complex (hPAFc) and its individual subunits have been implicated in human diseases, including cancer. However, its involvement in breast cancer awaits investigation. Using data mining and human breast cancer tissue microarrays, we found that Ctr9, the key scaffold subunit in hPAFc, is highly expressed in estrogen receptor α-positive (ERα + ) luminal breast cancer, and the high expression of Ctr9 correlates with poor prognosis. Knockdown of Ctr9 in ERα + breast cancer cells almost completely erased estrogen-regulated transcriptional response. At the molecular level, Ctr9 enhances ERα protein stability, promotes recruitment of ERα and RNAPII, and stimulates transcription elongation and transcription-coupled histone modifications. Knockdown of Ctr9, but not other hPAFc subunits, alters the morphology, proliferative capacity, and tamoxifen sensitivity of ERα + breast cancer cells. Together, our study reveals that Ctr9, a key subunit of hPAFc, is a central regulator of estrogen signaling that drives ERα + breast tumorigenesis, rendering it a potential target for the treatment of ERα + breast cancer.

show abstract

Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Ctr9 Regulates Estrogen-stimulated Transcription By Controllmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Zeng

2015

Genes Dev.

View full text Add to dashboard Cite

show abstract

“…19). The Paf1 complex associates with phos- phorylated and unphosphorylated Pol II, and it is found near promoters and along the ORFs of genes and detaches near the poly(A) site.…”

Section: Characterization Of a Reporter Of The Sty1-atf1mentioning

confidence: 99%

Genome-wide Screening of Regulators of Catalase Expression

Garcia¹,

Dedo²,

Ayté

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

In response to environmental cues, the mitogen-activated protein kinase Sty1-driven signaling cascade activates hundreds of genes to induce a robust anti-stress cellular response in fission yeast. Thus, upon stress imposition Sty1 transiently accumulates in the nucleus where it up-regulates transcription through the Atf1 transcription factor. Several regulators of transcription and translation have been identified as important to mount an integral response to oxidative stress, such as the SptAda-Gcn5-acetyl transferase or Elongator complexes, respectively. With the aim of identifying new regulators of this massive gene expression program, we have used a GFP-based protein reporter and screened a fission yeast deletion collection using flow cytometry. We find that the levels of catalase fused to GFP, both before and after a threat of peroxides, are altered in hundreds of strains lacking components of chromatin modifiers, transcription complexes, and modulators of translation. Thus, the transcription elongation complex Paf1, the histone methylase Set1-COMPASS, and the translation-related Trm112 dimers are all involved in full expression of Ctt1-GFP and in wild-type tolerance to peroxides.Cells adapt to changing environments by activating signaling pathways and modifying the cellular gene expression programs. Often, those signals are stressful and transiently or permanently halt cell growth. In particular, reactive oxygen species such as hydrogen peroxide (H 2 O 2 ) trigger what is known as oxidative stress. In fission yeast, Ͼ550 types of transcripts are up-regulated Ͼ2-fold in response to peroxides, and the expression of up to 450 genes is down-regulated also by Ͼ2-fold (1). This severe change in the Schizosaccharomyces pombe transcriptome is ruled by the mitogen-activated protein kinase Sty1-driven signaling cascade, which becomes activated upon different stress signals such as H 2 O 2 to allow adaptation and survival.Upon activation, Sty1 accumulates in the nucleus and orchestrates this massive change in the cell gene expression program. The downstream transcription factor Atf1 is important for this response. Atf1 is phosphorylated by Sty1 in a stressdependent manner, and transcription of genes occurs. We and others have demonstrated that the SAGA 4 complex is recruited to stress genes in a Sty1-and Atf1-dependent manner (2, 3) and participate in chromatin remodeling along stress open reading frames to allow RNA polymerase II (Pol II) initiation and elongation.For this dramatic change in the gene expression program to occur, not only the Pol II transcriptional machinery but also the translation process of the newly induced stress mRNAs has to be coordinated (4) and also be robust. Thus, we recently described that mutations in Elongator components impair wild-type tolerance to peroxides, probably by decreasing the amount of proteins synthesized from the stress mRNAs (5). Elongator introduces a modification of the anticodon loop of the low copy number tRNA UUU Lys as well as in other two types of tRNAs with a urac...

show abstract

CTR9‐mediated JAK2/STAT3 pathway promotes the proliferation, migration, and invasion of human glioma cells

Chen

et al. 2021

Clinical Laboratory Analysis

View full text Add to dashboard Cite

Background CTR9 (Cln three requiring 9) has been reported to be implicated in protein modification and oncogenesis of several human cancers. However, the protein expression and mechanism of CTR9 in glioma progression remain unclear. Methods We analyzed mRNA expression of CTR9 and CTR9‐related survival curves in the public database. Then, we detected CTR9 expression in glioma tissues and constructed U251 and U87 cells with stable silencing or overexpression of CTR9. Cell function tests and Western blot were conducted to explore the effects of CTR9 on glioma proliferation, invasion and migration, and the specific mechanism. All the date was presented as means ± SEM. Two‐sample t test and one‐way analysis of variance (ANOVA) were used to identify whether there was a significant difference between each group of data. Results We found that CTR9 was overexpressed in glioma and inversely associated with glioma patient survival. The results manifested that knockdown of CTR9 suppressed the proliferation, migration, and invasion of glioma cells, while overexpression facilitated them. The underlying molecular mechanism may involve the regulation of JAK2/STAT3 pathway by CTR9. Conclusion Our present study indicates that CTR9 is highly expressed in glioma and related to glioma grading and prognosis. CTR9 regulates malignant behaviors of glioma cells by activating JAK2/STAT3 pathway. Therefore, CTR9 may be a promising biomarker for the targeted therapy and prognosis evaluation of glioma.

show abstract

The many roles of the conserved eukaryotic Paf1 complex in regulating transcription, histone modifications, and disease states

Cited by 127 publications

References 177 publications

Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Ctr9, a key subunit of PAFc, affects global estrogen signaling and drives ERα-positive breast tumorigenesis

Genome-wide Screening of Regulators of Catalase Expression

CTR9‐mediated JAK2/STAT3 pathway promotes the proliferation, migration, and invasion of human glioma cells

Contact Info

Product

Resources

About