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Regulation of the ribosomal RNA transcription by c-MYC oncoprotein
Södertörn University, School of Life Sciences. Karolinska Institutet.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Stockholm: Karolinska Instiutet , 2006. , 52 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:sh:diva-31993ISBN: 91-7140-947-5 (print)OAI: oai:DiVA.org:sh-31993DiVA: diva2:1072789
Public defence
2006-12-21, MA636, Alfred Nobels allé 7, Huddinge, 10:00 (English)
Opponent
Supervisors
Available from: 2017-02-08 Created: 2017-02-08 Last updated: 2017-02-08Bibliographically approved
List of papers
1. Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels
Open this publication in new window or tab >>Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels
2003 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 116, no 9, 1707-1717 p.Article in journal (Refereed) Published
Abstract [en]

c-Myc is a predominately nuclear transcription factor that is a substrate for rapid turnover by the proteasome system. Cancer-related mutations in c-Myc lead to defects in its degradation and thereby contribute to the increase in its cellular level that is associated with the disease. Little is known about the mechanisms that target c-Myc to the proteasomes. By using a GFP fusion protein and live analysis we show that c-Myc shuttles between the nucleus and cytoplasm and thus it could be degraded in either compartment. Strikingly, at elevated levels of expression c-Myc accumulates at nucleoli in some cells, consistent with saturation of a nucleolus-associated degradation system in these cells. This idea is further supported by the observation that proteasome inhibitor treatment causes accumulation of c-Myc at the nucleoli of essentially all cells. Under these conditions c-Myc is relatively stably associated with the nucleolus, as would be expected if the nucleolus functions as a sequestration/degradation site for excess c-Myc. Furthermore, during elevated c-Myc expression or proteasome inhibition, nucleoli that are associated with c-Myc also accumulate proteasomes. c-Myc and proteasomes co-localise in intranucleolar regions distinct from the dense fibrillar component of the nucleolus. Based on these results we propose a model for c-Myc downregulation where c-Myc is sequestered at the nucleoli. Sequestration of c-Myc is accompanied by recruitment of proteasomes and may lead to subsequent degradation.

National Category
Cell Biology
Identifiers
urn:nbn:se:sh:diva-15546 (URN)10.1242/jcs.00370 (DOI)000182903600008 ()12665552 (PubMedID)2-s2.0-0037650101 (Scopus ID)
Available from: 2012-02-21 Created: 2012-02-21 Last updated: 2017-12-07Bibliographically approved
2. c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription
Open this publication in new window or tab >>c-Myc associates with ribosomal DNA and activates RNA polymerase I transcription
Show others...
2005 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 7, no 3, 303-310 p.Article in journal (Refereed) 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.

National Category
Cell Biology
Identifiers
urn:nbn:se:sh:diva-14389 (URN)10.1038/ncb1225 (DOI)000227329800019 ()15723053 (PubMedID)2-s2.0-20044375377 (Scopus ID)
Available from: 2011-12-22 Created: 2011-12-21 Last updated: 2017-12-08Bibliographically approved
3. Regulation of the nucleolar structure by the oncoprotein c-Myc and proteasomes
Open this publication in new window or tab >>Regulation of the nucleolar structure by the oncoprotein c-Myc and proteasomes
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
urn:nbn:se:sh:diva-31992 (URN)
Note

Som manuskript i avhandling. As manuscript in dissertation.

Available from: 2017-02-08 Created: 2017-02-08 Last updated: 2017-06-29Bibliographically approved

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Arabi, Azadeh

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