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Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation

Common hallmarks of cancer include the dysregulation of cell cycle progression and the acquisition of genome instability. In tumors, G1 cell cycle checkpoint induction is often lost. This increases the reliance on a functional G2/M checkpoint to prevent progression through mitosis with damaged DNA,...

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Autores principales: Skalka, George, Hall, Holly, Somers, Joanna, Bushell, Martin, Willis, Anne, Malewicz, Michal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527300/
https://www.ncbi.nlm.nih.gov/pubmed/30973299
http://dx.doi.org/10.1080/15384101.2019.1601476
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author Skalka, George
Hall, Holly
Somers, Joanna
Bushell, Martin
Willis, Anne
Malewicz, Michal
author_facet Skalka, George
Hall, Holly
Somers, Joanna
Bushell, Martin
Willis, Anne
Malewicz, Michal
author_sort Skalka, George
collection PubMed
description Common hallmarks of cancer include the dysregulation of cell cycle progression and the acquisition of genome instability. In tumors, G1 cell cycle checkpoint induction is often lost. This increases the reliance on a functional G2/M checkpoint to prevent progression through mitosis with damaged DNA, avoiding the introduction of potentially aberrant genetic alterations. Treatment of tumors with ionizing radiation (IR) utilizes this dependence on the G2/M checkpoint. Therefore, identification of factors which regulate this process could yield important biomarkers for refining this widely used cancer therapy. Leucine zipper and ICAT domain containing (LZIC) downregulation has been associated with the development of IR-induced tumors. However, despite LZIC being highly conserved, it has no known molecular function. We demonstrate that LZIC knockout (KO) cell lines show a dysregulated G2/M cell cycle checkpoint following IR treatment. In addition, we show that LZIC deficient cells competently activate the G1 and early G2/M checkpoint but fail to maintain the late G2/M checkpoint after IR exposure. Specifically, this defect was found to occur downstream of PIKK signaling. The LZIC KO cells demonstrated severe aneuploidy indicative of genomic instability. In addition, analysis of data from cancer patient databases uncovered a strong correlation between LZIC expression and poor prognosis in several cancers. Our findings suggest that LZIC is functionally involved in cellular response to IR, and its expression level could serve as a biomarker for patient stratification in clinical cancer practice.
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spelling pubmed-65273002019-05-29 Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation Skalka, George Hall, Holly Somers, Joanna Bushell, Martin Willis, Anne Malewicz, Michal Cell Cycle Research Paper Common hallmarks of cancer include the dysregulation of cell cycle progression and the acquisition of genome instability. In tumors, G1 cell cycle checkpoint induction is often lost. This increases the reliance on a functional G2/M checkpoint to prevent progression through mitosis with damaged DNA, avoiding the introduction of potentially aberrant genetic alterations. Treatment of tumors with ionizing radiation (IR) utilizes this dependence on the G2/M checkpoint. Therefore, identification of factors which regulate this process could yield important biomarkers for refining this widely used cancer therapy. Leucine zipper and ICAT domain containing (LZIC) downregulation has been associated with the development of IR-induced tumors. However, despite LZIC being highly conserved, it has no known molecular function. We demonstrate that LZIC knockout (KO) cell lines show a dysregulated G2/M cell cycle checkpoint following IR treatment. In addition, we show that LZIC deficient cells competently activate the G1 and early G2/M checkpoint but fail to maintain the late G2/M checkpoint after IR exposure. Specifically, this defect was found to occur downstream of PIKK signaling. The LZIC KO cells demonstrated severe aneuploidy indicative of genomic instability. In addition, analysis of data from cancer patient databases uncovered a strong correlation between LZIC expression and poor prognosis in several cancers. Our findings suggest that LZIC is functionally involved in cellular response to IR, and its expression level could serve as a biomarker for patient stratification in clinical cancer practice. Taylor & Francis 2019-04-19 /pmc/articles/PMC6527300/ /pubmed/30973299 http://dx.doi.org/10.1080/15384101.2019.1601476 Text en © 2019 MRC Toxicology Unit, University of Cambridge. Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Paper
Skalka, George
Hall, Holly
Somers, Joanna
Bushell, Martin
Willis, Anne
Malewicz, Michal
Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation
title Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation
title_full Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation
title_fullStr Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation
title_full_unstemmed Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation
title_short Leucine zipper and ICAT domain containing (LZIC) protein regulates cell cycle transitions in response to ionizing radiation
title_sort leucine zipper and icat domain containing (lzic) protein regulates cell cycle transitions in response to ionizing radiation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527300/
https://www.ncbi.nlm.nih.gov/pubmed/30973299
http://dx.doi.org/10.1080/15384101.2019.1601476
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