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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...

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Autores principales: Nor Rashid, Nurshamimi, Yong, Zi Ling, Yusof, Rohana, Watson, Roger J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
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.
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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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