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HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block
BACKGROUND: Retinoblastoma like protein 2 (RBL2) or p130 is a member of the pocket protein family, which is infrequently mutated in human tumours. Its expression is posttranscriptionally regulated and largely G0 restricted. We have previously shown that E6/E7 oncoproteins encoded by human papillomav...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700559/ https://www.ncbi.nlm.nih.gov/pubmed/26728921 http://dx.doi.org/10.1186/s12985-015-0460-8 |
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author | Nor Rashid, Nurshamimi Yong, Zi Ling Yusof, Rohana Watson, Roger J. |
author_facet | Nor Rashid, Nurshamimi Yong, Zi Ling Yusof, Rohana Watson, Roger J. |
author_sort | Nor Rashid, Nurshamimi |
collection | PubMed |
description | BACKGROUND: Retinoblastoma like protein 2 (RBL2) or p130 is a member of the pocket protein family, which is infrequently mutated in human tumours. Its expression is posttranscriptionally regulated and largely G0 restricted. We have previously shown that E6/E7 oncoproteins encoded by human papillomavirus (HPV) type 16, which is a high-risk type for cervical cancer development, must target p130 to promote the host cell to exit from quiescence (G0) state and enter S phase of the cell cycle. P130 is associated with the DREAM (DP, RB-like, E2F and MuvB) complex in G0/G1, which prevents S phase progression by repressing transcription of E2F-regulated genes. E7 proteins could potentially disrupt the p130-DREAM complex through two known mechanisms: direct interaction with p130 or induction of cyclin dependent kinase 2 (CDK2) phosphorylation by interacting with its inhibitor, p21(CIP1). METHODS: In this study we have used p130 mutants deficient in binding the E7 LXCXE domain (p130mE7), unphosphorylatable by CDK2 (p130PM22) or a combination of both (p130PM22/mE7) to investigate these mechanisms used by E7 proteins to disrupt the p130-DREAM complex and promote cell cycle progression. RESULTS: We found that HPV16 E7 binding to p130 through its LXCXE domain was absolutely required to disrupt p130-DREAM to promote S phase of the cell cycle, as HPV16 E7 was unable to suppress p130mE7 but could suppress p130PM22. In contrast, the E7 protein encoded by a cutaneous HPV type that lacks a functional LXCXE domain, HPV 48 E7, was also able to disrupt p130-DREAM to promote cell cycling, but through the alternative mechanism. Thus, HPV48 E7 could suppress a cell cycle block imposed by p130mE7, but was unable to suppress p130PM22. CONCLUSIONS: Overall, these results indicate that suppression of p130 is required for HPV-induced cell cycling, and that different HPV E7 proteins can use alternative mechanisms to achieve this. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12985-015-0460-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4700559 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-47005592016-01-06 HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block Nor Rashid, Nurshamimi Yong, Zi Ling Yusof, Rohana Watson, Roger J. Virol J Short Report BACKGROUND: Retinoblastoma like protein 2 (RBL2) or p130 is a member of the pocket protein family, which is infrequently mutated in human tumours. Its expression is posttranscriptionally regulated and largely G0 restricted. We have previously shown that E6/E7 oncoproteins encoded by human papillomavirus (HPV) type 16, which is a high-risk type for cervical cancer development, must target p130 to promote the host cell to exit from quiescence (G0) state and enter S phase of the cell cycle. P130 is associated with the DREAM (DP, RB-like, E2F and MuvB) complex in G0/G1, which prevents S phase progression by repressing transcription of E2F-regulated genes. E7 proteins could potentially disrupt the p130-DREAM complex through two known mechanisms: direct interaction with p130 or induction of cyclin dependent kinase 2 (CDK2) phosphorylation by interacting with its inhibitor, p21(CIP1). METHODS: In this study we have used p130 mutants deficient in binding the E7 LXCXE domain (p130mE7), unphosphorylatable by CDK2 (p130PM22) or a combination of both (p130PM22/mE7) to investigate these mechanisms used by E7 proteins to disrupt the p130-DREAM complex and promote cell cycle progression. RESULTS: We found that HPV16 E7 binding to p130 through its LXCXE domain was absolutely required to disrupt p130-DREAM to promote S phase of the cell cycle, as HPV16 E7 was unable to suppress p130mE7 but could suppress p130PM22. In contrast, the E7 protein encoded by a cutaneous HPV type that lacks a functional LXCXE domain, HPV 48 E7, was also able to disrupt p130-DREAM to promote cell cycling, but through the alternative mechanism. Thus, HPV48 E7 could suppress a cell cycle block imposed by p130mE7, but was unable to suppress p130PM22. CONCLUSIONS: Overall, these results indicate that suppression of p130 is required for HPV-induced cell cycling, and that different HPV E7 proteins can use alternative mechanisms to achieve this. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12985-015-0460-8) contains supplementary material, which is available to authorized users. BioMed Central 2016-01-04 /pmc/articles/PMC4700559/ /pubmed/26728921 http://dx.doi.org/10.1186/s12985-015-0460-8 Text en © Nor Rashid et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Short Report Nor Rashid, Nurshamimi Yong, Zi Ling Yusof, Rohana Watson, Roger J. HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block |
title | HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block |
title_full | HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block |
title_fullStr | HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block |
title_full_unstemmed | HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block |
title_short | HPV 16E7 and 48E7 proteins use different mechanisms to target p130 to overcome cell cycle block |
title_sort | hpv 16e7 and 48e7 proteins use different mechanisms to target p130 to overcome cell cycle block |
topic | Short Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700559/ https://www.ncbi.nlm.nih.gov/pubmed/26728921 http://dx.doi.org/10.1186/s12985-015-0460-8 |
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