MYC and MNT in transcriptional regulation and chromatin dynamics
Author: Wahlström, Therese
Date: 2014-02-21
Location: Petrénsalen, Nobels väg 12B, Karolinska Institutet, Campus Solna
Time: 09.30
Department: Inst för mikrobiologi, tumör- och cellbiologi / Dept of Microbiology, Tumor and Cell Biology
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Thesis (7.307Mb)
Abstract
The MYC proto-oncogene regulates several cellular processes including cell cycle progression, proliferation, apoptosis and differentiation. In normal cells, MYC expression is induced upon cell cycle entry and is thereafter expressed at low levels during proliferation. In contrast, MYC is de-regulated in the majority of human tumors and contributes to uncontrolled cell proliferation and immortalization. Both MYC and its antagonist MNT are transcription factors that bind to the same E-box sequences in target promoters as heterodimers with the MAX protein. Whereas MYC/MAX activates transcription by recruitment of co-factors containing histone acetyltransferase (HAT) activity, MNT/MAX interacts with the adaptor-protein SIN 3 and recruits histone deacetyltransferases (HDAC) in order to repress transcription.
In this thesis I have studied MYC and MNT in transcriptional regulation and chromatin dynamics. More specifically, we demonstrated MNT to be a transcriptional repressor that is functionally regulated by mitogen-activated protein kinase (MAPK) induced phosphorylation at cell cycle entry. In turn, we showed that this phosphorylation inhibited MNT-mSIN 3 interaction and recruitment of HDAC activity. In addition, relief of MNT-mediated transcriptional repression allowed activation of MYC target genes (Paper I). Phosphorylation at MNT S70 was shown to generate the 74 kDa form of the MNT protein, which was induced upon serum stimulation of quiescent cells (Paper I and II). However, the S70 phosphorylation did not inhibit MNT as a transcriptional repressor but was instead shown to regulate MNT protein stability. Interestingly, MYC/RAS induced cellular transformation was increased in cells expressing a mutant mimicking constitutive phosphorylat ion of MNT S70. Higher levels of MNT in these cells were suggested to antagonize both pro-proliferative and pro-apoptotic activities mediated by MYC (Paper II) . Importantly, we have also found that MNT represses transcription by de-acetylation of histone tails and complete chromatin condensation. In contrast, we confirmed binding of MYC to active chromatin and its involvement in fine-tuning of gene expression. Our data show that MYC once bound to the promoter induces local hyper-acetylation and increased DNA accessibility, which allows transcriptional activation (Paper III).
Finally, we demonstrated transcriptional upregulation of the miR-17-92 cluster in neuroblastoma cells overexpressing the MYC family member MYCN. Two members of this cluster, miR-18a and miR-19a, was shown to interfere with the expression of the transcription factor estrogen receptor-α (ESR1). Based on our data we suggest that MYCN promotes tumorigenesis and development of neuroblastoma by preventing normal neuroblast differentiation through indirect regulation of ESR1 expression (Paper IV) .
Taken together, the interplay between MYC and MNT regulate gene expression important for cellular activities, which will determine the biological outcome.
In this thesis I have studied MYC and MNT in transcriptional regulation and chromatin dynamics. More specifically, we demonstrated MNT to be a transcriptional repressor that is functionally regulated by mitogen-activated protein kinase (MAPK) induced phosphorylation at cell cycle entry. In turn, we showed that this phosphorylation inhibited MNT-mSIN 3 interaction and recruitment of HDAC activity. In addition, relief of MNT-mediated transcriptional repression allowed activation of MYC target genes (Paper I). Phosphorylation at MNT S70 was shown to generate the 74 kDa form of the MNT protein, which was induced upon serum stimulation of quiescent cells (Paper I and II). However, the S70 phosphorylation did not inhibit MNT as a transcriptional repressor but was instead shown to regulate MNT protein stability. Interestingly, MYC/RAS induced cellular transformation was increased in cells expressing a mutant mimicking constitutive phosphorylat ion of MNT S70. Higher levels of MNT in these cells were suggested to antagonize both pro-proliferative and pro-apoptotic activities mediated by MYC (Paper II) . Importantly, we have also found that MNT represses transcription by de-acetylation of histone tails and complete chromatin condensation. In contrast, we confirmed binding of MYC to active chromatin and its involvement in fine-tuning of gene expression. Our data show that MYC once bound to the promoter induces local hyper-acetylation and increased DNA accessibility, which allows transcriptional activation (Paper III).
Finally, we demonstrated transcriptional upregulation of the miR-17-92 cluster in neuroblastoma cells overexpressing the MYC family member MYCN. Two members of this cluster, miR-18a and miR-19a, was shown to interfere with the expression of the transcription factor estrogen receptor-α (ESR1). Based on our data we suggest that MYCN promotes tumorigenesis and development of neuroblastoma by preventing normal neuroblast differentiation through indirect regulation of ESR1 expression (Paper IV) .
Taken together, the interplay between MYC and MNT regulate gene expression important for cellular activities, which will determine the biological outcome.
List of papers:
I. Nikita Popov, Therese Wahlström, Peter J. Hurlin, and Marie Henriksson. Mnt transcriptional repressor is functionally regulated during cell cycle progression. Oncogene. 2005, 24(56):8326-37.
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II. Therese Wahlström, Craig William Hooker, Katannya Kapeli, Sara Ota, Roel van Eijk, Marie Arsenian Henriksson, and Peter J. Hurlin. Phosphorylation at serine 70 controls MNT accumulation and MYC-dependent cell transformation. 2014. [Manuscript]
III. Therese Wahlström, Sergey Belikov, and Marie Arsenian Henriksson. Chromatin dynamics at the hTERT promoter during transcriptional activation and repression by c-Myc and Mnt in Xenopus leavisoocytes. Experimental Cell Research. 2013, 319(20): 3160-9.
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IV. Jakob Lovén, Nikolay Zinin, Therese Wahlström, Inga Müller, Petter Brodin, Erik Fredlund, Ulf Ribacke, Andor Pivarcsi, Sven Påhlman, and Marie Henriksson. MYCN-regulated microRNAs repress estrogen receptor-α (ESR1) expression and neuronal differentiation in human neuroblastoma. Proceeding of the National Academy of Science. 2010, 107(4): 1553-8.
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I. Nikita Popov, Therese Wahlström, Peter J. Hurlin, and Marie Henriksson. Mnt transcriptional repressor is functionally regulated during cell cycle progression. Oncogene. 2005, 24(56):8326-37.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Therese Wahlström, Craig William Hooker, Katannya Kapeli, Sara Ota, Roel van Eijk, Marie Arsenian Henriksson, and Peter J. Hurlin. Phosphorylation at serine 70 controls MNT accumulation and MYC-dependent cell transformation. 2014. [Manuscript]
III. Therese Wahlström, Sergey Belikov, and Marie Arsenian Henriksson. Chromatin dynamics at the hTERT promoter during transcriptional activation and repression by c-Myc and Mnt in Xenopus leavisoocytes. Experimental Cell Research. 2013, 319(20): 3160-9.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. Jakob Lovén, Nikolay Zinin, Therese Wahlström, Inga Müller, Petter Brodin, Erik Fredlund, Ulf Ribacke, Andor Pivarcsi, Sven Påhlman, and Marie Henriksson. MYCN-regulated microRNAs repress estrogen receptor-α (ESR1) expression and neuronal differentiation in human neuroblastoma. Proceeding of the National Academy of Science. 2010, 107(4): 1553-8.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Arsenian Henriksson, Marie
Issue date: 2014-01-31
Rights:
Publication year: 2014
ISBN: 978-91-7549-377-0
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