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Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells

Ultraconserved regions (UCRs) are >200 bp genomic segments with perfect human-to-rodent sequence identity. Transcribed UCRs constitute a new category of noncoding RNAs whose functions remain poorly understood. The human transformer 2β (TRA2B) gene contains a 419-bp UCR spanning the 276-bp exon 2...

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Autores principales: Kajita, K, Kuwano, Y, Satake, Y, Kano, S, Kurokawa, K, Akaike, Y, Masuda, K, Nishida, K, Rokutan, K
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848834/
https://www.ncbi.nlm.nih.gov/pubmed/27043659
http://dx.doi.org/10.1038/oncsis.2016.18
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author Kajita, K
Kuwano, Y
Satake, Y
Kano, S
Kurokawa, K
Akaike, Y
Masuda, K
Nishida, K
Rokutan, K
author_facet Kajita, K
Kuwano, Y
Satake, Y
Kano, S
Kurokawa, K
Akaike, Y
Masuda, K
Nishida, K
Rokutan, K
author_sort Kajita, K
collection PubMed
description Ultraconserved regions (UCRs) are >200 bp genomic segments with perfect human-to-rodent sequence identity. Transcribed UCRs constitute a new category of noncoding RNAs whose functions remain poorly understood. The human transformer 2β (TRA2B) gene contains a 419-bp UCR spanning the 276-bp exon 2 and its neighboring introns. TRA2B exon 2 has premature stop codons, whereas an exon 2-containing splice variant (TRA2β4) was expressed preferentially in the nuclei of human colon cancer cells. TRA2β4 knockdown p53-independently stimulated CDKN1A transcription and increased p21, resulting in the appearance of senescent cells. Biotin pull-down and RNA immunoprecipitation assays revealed that TRA2β4 interacted with Sp1 through a Sp1-binding sequence (485-GGGG-488) in a stem-loop structure of exon 2. Mutation of this sequence (485-AAGG-488) disrupted the stem-loop structure, blocked the interaction with Sp1 and increased CDKN1A transcription. Overexpression of TRA2β4 significantly decreased CDKN1A mRNA levels and accelerated cell growth, but the introduction of the mutation in the Sp1-binding sequence completely canceled these effects. Taken together, TRA2β4 may sequester Sp1 from occupying promoters of target genes including CDKN1A, promoting cell growth by interrupting the senescence-related gene expression program. This novel function of TRA2β4 may uncover an oncogenic function of transcribed UCRs.
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spelling pubmed-48488342016-05-09 Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells Kajita, K Kuwano, Y Satake, Y Kano, S Kurokawa, K Akaike, Y Masuda, K Nishida, K Rokutan, K Oncogenesis Original Article Ultraconserved regions (UCRs) are >200 bp genomic segments with perfect human-to-rodent sequence identity. Transcribed UCRs constitute a new category of noncoding RNAs whose functions remain poorly understood. The human transformer 2β (TRA2B) gene contains a 419-bp UCR spanning the 276-bp exon 2 and its neighboring introns. TRA2B exon 2 has premature stop codons, whereas an exon 2-containing splice variant (TRA2β4) was expressed preferentially in the nuclei of human colon cancer cells. TRA2β4 knockdown p53-independently stimulated CDKN1A transcription and increased p21, resulting in the appearance of senescent cells. Biotin pull-down and RNA immunoprecipitation assays revealed that TRA2β4 interacted with Sp1 through a Sp1-binding sequence (485-GGGG-488) in a stem-loop structure of exon 2. Mutation of this sequence (485-AAGG-488) disrupted the stem-loop structure, blocked the interaction with Sp1 and increased CDKN1A transcription. Overexpression of TRA2β4 significantly decreased CDKN1A mRNA levels and accelerated cell growth, but the introduction of the mutation in the Sp1-binding sequence completely canceled these effects. Taken together, TRA2β4 may sequester Sp1 from occupying promoters of target genes including CDKN1A, promoting cell growth by interrupting the senescence-related gene expression program. This novel function of TRA2β4 may uncover an oncogenic function of transcribed UCRs. Nature Publishing Group 2016-04 2016-04-04 /pmc/articles/PMC4848834/ /pubmed/27043659 http://dx.doi.org/10.1038/oncsis.2016.18 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Oncogenesis is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Kajita, K
Kuwano, Y
Satake, Y
Kano, S
Kurokawa, K
Akaike, Y
Masuda, K
Nishida, K
Rokutan, K
Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells
title Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells
title_full Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells
title_fullStr Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells
title_full_unstemmed Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells
title_short Ultraconserved region-containing Transformer 2β4 controls senescence of colon cancer cells
title_sort ultraconserved region-containing transformer 2β4 controls senescence of colon cancer cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848834/
https://www.ncbi.nlm.nih.gov/pubmed/27043659
http://dx.doi.org/10.1038/oncsis.2016.18
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