Please use this identifier to cite or link to this item: https://doi.org/10.1186/1476-4598-13-54
Title: Regulation of CDKN2B expression by interaction of Arnt with Miz-1 - a basis for functional integration between the HIF and Myc gene regulatory pathways
Authors: Aesoy, R.
Gradin, K.
Aasrud, K.S.
Hoivik, E.A.
Ruas, J.L.
Poellinger, L. 
Bakke, M.
Keywords: Arnt
CDKN2B
Helix-loop-helix transcription factors
Hypoxia
Hypoxia-inducible factor (HIF)
Miz-1
Myc
Issue Date: 11-Mar-2014
Citation: Aesoy, R., Gradin, K., Aasrud, K.S., Hoivik, E.A., Ruas, J.L., Poellinger, L., Bakke, M. (2014-03-11). Regulation of CDKN2B expression by interaction of Arnt with Miz-1 - a basis for functional integration between the HIF and Myc gene regulatory pathways. Molecular Cancer 13 (1) : -. ScholarBank@NUS Repository. https://doi.org/10.1186/1476-4598-13-54
Abstract: Background: Hypoxia- and Myc-dependent transcriptional regulatory pathways are frequently deregulated in cancer cells. These pathways converge in many cellular responses, but the underlying molecular mechanisms are unclear.Methods: The ability of Miz-1 and Arnt to interact was identified in a yeast two-hybrid screen. The mode of interaction and the functional consequences of complex formation were analyzed by diverse molecular biology methods, in vitro. Statistical analyses were performed by Student's t-test and ANOVA.Results: In the present study we demonstrate that the aryl hydrocarbon receptor nuclear translocator (Arnt), which is central in hypoxia-induced signaling, forms a complex with Miz-1, an important transcriptional regulator in Myc-mediated transcriptional repression. Overexpression of Arnt induced reporter gene activity driven by the proximal promoter of the cyclin-dependent kinase inhibitor 2B gene (CDKN2B), which is an established target for the Myc/Miz-1 complex. In contrast, mutated forms of Arnt, that were unable to interact with Miz-1, had reduced capability to activate transcription. Moreover, repression of Arnt reduced endogenous CDKN2B expression, and chromatin immunoprecipitation demonstrated that Arnt interacts with the CDKN2B promoter. The transcriptional activity of Arnt was counteracted by Myc, but not by a mutated variant of Myc that is unable to interact with Miz-1, suggesting mutually exclusive interaction of Arnt and Myc with Miz-1. Our results also establish CDKN2B as a hypoxia regulated gene, as endogenous CDKN2B mRNA and protein levels were reduced by hypoxic treatment of U2OS cells.Conclusions: Our data reveal a novel mode of regulation by protein-protein interaction that directly ties together, at the transcriptional level, the Myc- and hypoxia-dependent signaling pathways and expands our understanding of the roles of hypoxia and cell cycle alterations during tumorigenesis. © 2014 Aesoy et al.; licensee BioMed Central Ltd.
Source Title: Molecular Cancer
URI: http://scholarbank.nus.edu.sg/handle/10635/115903
ISSN: 14764598
DOI: 10.1186/1476-4598-13-54
Appears in Collections:Staff Publications

Show full item record
Files in This Item:
There are no files associated with this item.

SCOPUSTM   
Citations

4
checked on Jun 18, 2018

WEB OF SCIENCETM
Citations

1
checked on Jun 11, 2018

Page view(s)

33
checked on Jun 22, 2018

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.