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c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription
Södertörns högskola, Institutionen för livsvetenskaper. Karolinska Institutet.
SLU.
SLU.
German Cancer Research Center, Heidelberg, Germany.
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2005 (Engelska)Ingår i: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 7, nr 3, s. 303-310Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The c-Myc oncoprotein regulates transcription of genes that are associated with cell growth, proliferation and apoptosis(1). c-Myc levels are modulated by ubiquitin/proteasome-mediated degradation(1). Proteasome inhibition leads to c-Myc accumulation within nucleoli(2), indicating that c-Myc might have a nucleolar function. Here we show that the proteins c-Myc and Max interact in nucleoli and are associated with ribosomal DNA. This association is increased upon activation of quiescent cells and is followed by recruitment of the Myc cofactor TRRAP, enhanced histone acetylation, recruitment of RNA polymerase I (Pol I), and activation of rDNA transcription. Using small interfering RNAs (siRNAs) against c-Myc and an inhibitor of Myc - Max interactions, we demonstrate that c-Myc is required for activating rDNA transcription in response to mitogenic signals. Furthermore, using the ligand-activated MycER ( ER, oestrogen receptor) system, we show that c-Myc can activate Pol I transcription in the absence of Pol II transcription. These results suggest that c-Myc coordinates the activity of all three nuclear RNA polymerases, and thereby plays a key role in regulating ribosome biogenesis and cell growth.

Ort, förlag, år, upplaga, sidor
2005. Vol. 7, nr 3, s. 303-310
Nationell ämneskategori
Cellbiologi
Identifikatorer
URN: urn:nbn:se:sh:diva-14389DOI: 10.1038/ncb1225ISI: 000227329800019PubMedID: 15723053Scopus ID: 2-s2.0-20044375377OAI: oai:DiVA.org:sh-14389DiVA, id: diva2:469143
Tillgänglig från: 2011-12-22 Skapad: 2011-12-21 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ingår i avhandling
1. Role of c-Myc in the regulation of rDNA transcription by RNA polymerase I
Öppna denna publikation i ny flik eller fönster >>Role of c-Myc in the regulation of rDNA transcription by RNA polymerase I
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Ribosomal biogenesis and protein translation are finely coordinated with cell proliferation. All three RNA polymerases Pol I, II, and III are utilized for highly efficient and accurate ribosome production. The transcriptional activity of Pol I has been found to be a key determinant for ribosome biogenesis. As an immediate early gene, Myc can orchestrate the transcriptional activities of all RNA polymerases upon mitogenic stimulation. The direct roles of Myc-mediated Pol II & III transcription have been well studied, but that of Myc-mediated Pol I transcription remains unclear. Here we show that Myc with its obligatory partner Max colocalizes in nucleoli and Myc binds to ribosomal DNA, and that association of Myc to rDNA is followed by recruitment of the cofactor TRRAP which enhances histone acetylation. Using the ligand-activated MycE system, we also showed that c-Myc could activate Pol I transcription in the absence of Pol II transcription. Furthermore, using a model system of cell lines with variable Myc status, we showed that Myc rapidly induced gene loop structures in rDNA chromatin which juxtaposes upstream and downstream rDNA sequences. In addition, the origins of two or more rDNA gene loops are closely juxtaposed, suggesting the possibility that Myc induces nucleolar chromatin hubs. Next, we investigated the role of Myc in chromatin domain organization of rRNA genes and the compartmentalized distribution of nucleoli, and found that Myc mediated a spatial organization of mammalian rRNA genes into distinct chromatin loops by tethering to nucleolar matrix via their 5 and 3 nontranscribed spacer sequences. We found evidence that Myc corporated with co-activators to become a regulatory complex that governed the transcription of rRNA by orchestrating dynamic chromatin-loop architecture. Finally, we demonstrated that Myc plays a role in the overall structural integrity of the nucleolus and that Myc antagonized its antagonistic partner Mad1 programming the epigenetic status of rDNA chromatin. These changes are discussed in relation to current knowledge about nucleolar structure as well as the organization of chromosomes and transcription factories in nuclear regions outside the nucleolus.

Ort, förlag, år, upplaga, sidor
Stockholm: Karolinska Institutet, 2010. s. 59
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:sh:diva-30693 (URN)978-91-7409-948-5 (ISBN)
Handledare
Tillgänglig från: 2016-08-04 Skapad: 2016-08-04 Senast uppdaterad: 2016-08-04Bibliografiskt granskad
2. Regulation of the ribosomal RNA transcription by c-MYC oncoprotein
Öppna denna publikation i ny flik eller fönster >>Regulation of the ribosomal RNA transcription by c-MYC oncoprotein
2006 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The transcription factor c-Myc is a key regulator of growth and proliferation. c-Myc levels are tightly controlled and deregulated c-Myc is often associated with human cancers. In our initial studies we observed that upon inhibition of proteasomes, excess c-Myc accumulates primarily in the nucleoli. After further investigation we could show that c-Myc binds to and activates RNA polymerase I-mediated transcription of the ribosomal RNA (rRNA) genes located in the nucleoli and that proteasomes are involved in this process. We demonstrate that upon an increase in c-Myc levels through either inhibition of the proteasomes or high expression, c-Myc accumulates in the nucleoli. The dynamics of the nucleoplasmic and the nucleolar c-Myc was studied in living cells expressing GFP-fused cMyc using the Fluorescent loss in photo-bleaching and the Fluorescent recovery after photobleaching techniques. We show that c-Myc is relatively stably associated with the nucleoli. In addition, we show that proteasomes accumulate and co-localise with nucleolar c-Myc. We further investigate the function of c-Myc in the nucleoli and show that c-Myc and Max interact in the nucleoli and are associated with the ribosomal DNA. Upon mitogenic stimulation of quiescent human lymphocytes c-Myc is recruited to the rRNA genes together with pol I. Association of c-Myc with the rDNA is also accompanied by an increase in rDNA histone acetylation and activation of rRNA transcription. Inhibition of c-Myc inhibits rRNA transcription. These results suggest that c-Myc plays a key role in regulating ribosome biogenesis and thus cell growth. We also show that proteasomes are required for activation of rRNA transcription, even though c-Myc levels increase in response to reduced proteasome activity. The role of proteasomes in rDNA transcription remains to be determined. We also investigate the role of c-Myc in regulation of the nucleolar organisation and induction of nucleolar alterations in cancer cells. Several types of human cancers with nucleolar alterations including cancers of blood, prostate and breast are also associated with deregulated levels of c-Myc. However, it is not known whether c-Myc contributes to the induction of nucleolar changes in these cancers. We show that despite high levels, c-Myc does not accumulate in the nucleoli in lymphoma and breast cancer cell lines. This is intriguing since nucleolar accumulation of excess c-Myc in other cell lines is associated with inhibition of rRNA transcription.

Ort, förlag, år, upplaga, sidor
Stockholm: Karolinska Instiutet, 2006. s. 52
Nationell ämneskategori
Biologiska vetenskaper
Identifikatorer
urn:nbn:se:sh:diva-31993 (URN)91-7140-947-5 (ISBN)
Disputation
2006-12-21, MA636, Alfred Nobels allé 7, Huddinge, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-02-08 Skapad: 2017-02-08 Senast uppdaterad: 2017-02-08Bibliografiskt granskad

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Arabi, AzadehShiue, ChiounanWright, Anthony P H

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