Regulation of Telomerase by Human Papillomaviruses

Galloway, Denise A.; Gewin, Lindy; Luo, Wenhua; Grandori, Carla; Myers, H.F.; Kiyono, Tohru; Klingelhutz, Aloysius J.; McDougall, James K.

doi:10.1101/sqb.2004.70.25

Cited by 3 publications

(11 citation statements)

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“…However, as demonstrated in studies of small interfering RNA (siRNA) knockdown, hTERT transactivation by E6 requires the cellular ubiquitin ligase E6AP as well as Myc (12,14,30,58). We have also shown that E6 and Myc associate in vivo and bind coordinately with promoter activation to the hTERT promoter in primary human foreskin keratinocytes (HFKs) (58).…”

mentioning

confidence: 85%

“…The HPV-16 E6 and E7 genes are necessary and sufficient to immortalize primary HFKs and ectocervical keratinocytes (20,38). While E6 directs the ubiquitin-dependent degradation of p53, it also has functions that are p53 independent, including telomerase activation and cell transformation (12,35,36). To determine whether the immortalizing activity of E6 and E7 correlated with tumor suppressor inactivation or telomerase induction, we used retroviruses to generate cell strains expressing an empty retroviral vector (pLXSN), E6 (pLXSN-16E6), E7 (pLXSN-16E7), or E6 and E7 (pLXSN-16E6E7), as described in Materials and Methods.…”

Section: E6mentioning

confidence: 99%

“…Our previous studies and those of other laboratories have shown that E6-mediated hTERT transactivation is independent of p53 degradation and interactions with PDZ proteins (12,14,22,26,30). However, as demonstrated in studies of small interfering RNA (siRNA) knockdown, hTERT transactivation by E6 requires the cellular ubiquitin ligase E6AP as well as Myc (12,14,30,58).…”

mentioning

confidence: 93%

“…The absence of telomerase activity in most normal human cells results in the progressive shortening of telomeres with each cell division (19,56,60), eventuating in growth arrest or replicative senescence (6,19). In contrast to most human somatic cells, immortalized and cancer cells contain detectable telomerase activity and consequently maintain their telomere length and proliferative potential (18,25,52,63).Our previous studies and those of other laboratories have shown that E6-mediated hTERT transactivation is independent of p53 degradation and interactions with PDZ proteins (12,14,22,26,30). However, as demonstrated in studies of small interfering RNA (siRNA) knockdown, hTERT transactivation by E6 requires the cellular ubiquitin ligase E6AP as well as Myc (12,14,30,58).…”

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confidence: 99%

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Cell-Restricted Immortalization by Human Papillomavirus Correlates with Telomerase Activation and Engagement of the hTERT Promoter by Myc

Dakić

Chen

et al. 2008

J Virol

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The high-risk human papillomaviruses (HPVs) are the causative agents of nearly all cervical cancers and are etiologically linked to additional human cancers, including those of anal, oral, and laryngeal origin. The main transforming genes of the high-risk HPVs are E6 and E7. E6, in addition to its role in p53 degradation, induces hTERT mRNA transcription in genital keratinocytes via interactions with Myc protein, thereby increasing cellular telomerase activity. While the HPV type 16 E6 and E7 genes efficiently immortalize human keratinocytes, they appear to only prolong the life span of human fibroblasts. To examine the molecular basis for this cell-type dependency, we examined the correlation between the ability of E6 to transactivate endogenous and exogenous hTERT promoters and to immortalize genital keratinocytes and fibroblasts. Confirming earlier studies, the E6 and E7 genes were incapable of immortalizing human fibroblasts but did delay senescence. Despite the lack of immortalization, E6 was functional in the fibroblasts, mediating p53 degradation and strongly transactivating an exogenous hTERT promoter. However, E6 failed to transactivate the endogenous hTERT promoter. Coordinately with this failure, we observed that Myc protein was not associated with the endogenous hTERT promoter, most likely due to the extremely low level of Myc expression in these cells and/or to differences in chromatin structure, in contrast with hTERT promoters that we found to be activated by E6 (i.e., the endogenous hTERT promoter in primary keratinoctyes and the exogenous hTERT core promoter in fibroblasts), where Myc is associated with the promoter in either a quiescent or an E6-induced state. These findings are consistent with those of our previous studies on mutagenesis and the knockdown of small interfering RNA, which demonstrated a requirement for Myc in the induction of the hTERT promoter by E6 and suggested that occupancy of the promoter by Myc determines the responsiveness of E6 and the downstream induction of telomerase and cell immortalization.The high-risk papillomaviruses (HPVs; e.g., HPV type 16 and HPV-18) are associated with anogenital carcinomas (65, 66), laryngeal carcinomas, and head and neck carcinomas (15). These HPVs carry two oncogenes, E6 and E7, which are retained and expressed in HPV-positive cervical cancers (1, 2, 50) and are required for maintenance of the tumorigenic phenotype (35, 36). The E6 and E7 proteins were first identified as targeting the p53 and Rb tumor suppressor pathways in host cells (8,9,35,36,47,48), thereby disrupting cell cycle controls.Telomerase is a specialized reverse transcriptase that synthesizes repeat DNA sequences at the ends of chromosomes termed telomeres (17). The absence of telomerase activity in most normal human cells results in the progressive shortening of telomeres with each cell division (19,56,60), eventuating in growth arrest or replicative senescence (6,19). In contrast to most human somatic cells, immortalized and cancer cells contain detectable telomerase ac...

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confidence: 85%

Section: E6mentioning

confidence: 99%

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confidence: 93%

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confidence: 99%

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Cell-Restricted Immortalization by Human Papillomavirus Correlates with Telomerase Activation and Engagement of the hTERT Promoter by Myc

Dakić

Chen

et al. 2008

J Virol

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“…For example, expression of HPV16 E6 in the skin of transgenic mice induces malignant skin tumors, and this is independent of p53 genotype [14]. E6 also induces telomerase activity [15,16], which is generally associated with cancerderived cells. E6-induced telomerase activation requires E6AP, as demonstrated by the loss of telomerase activity following siRNA knockdown of E6AP [17,18].…”

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confidence: 99%

HPV E6, E6AP and Cervical Cancer

Beaudenon¹

2007

TPdb

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Every year, approximately 470,000 new cases of cervical cancer are diagnosed and approximately 230,000 women worldwide die of the disease, with the majority (~80%) of these cases and deaths occurring in developing countries. Human papillomaviruses (HPVs) are the etiological agents in nearly all cases (99.7%) of cervical cancer, and the HPV E6 protein is one of two viral oncoproteins that is expressed in virtually all HPV-positive cancers. E6 hijacks a cellular ubiquitin ligase, E6AP, resulting in the ubiquitylation and degradation of the p53 tumor suppressor, as well as several other cellular proteins. While the recent introduction of prophylactic vaccines against specific HPV types offers great promise for prevention of cervical cancer, there remains a need for therapeutics. Biochemical characterization of E6 and E6AP has suggested approaches for interfering with the activities of these proteins that could be useful for this purpose. Publication history:Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com). Protein pathway involvement in disease BackgroundHuman papillomaviruses (HPVs) are small DNA tumor viruses that infect cutaneous or mucosal epithelial cells, causing papillomas or warts on skin, genital tissues and the upper promyelocytic leukemia respiratory tract [1]. More than a hundred different HPV types have been characterized, and approximately a third of these infect the genital tract [2]. The genital HPV types are sexually transmitted and can be further divided into low-risk and highrisk groups according to the propensity of their induced lesions to progress to malignancy. The low-risk HPV types, such as types 6 and 11, are associated with genital warts that do not progress toward cancer, while the high-risk HPV types cause intraepithelial lesions that can progress to invasive carcinomas [3]. High-risk HPV types are associated with 99.7% of cervical cancers [4,5]. Specifically,

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Molecular Mechanisms of Human Papillomavirus-Induced Carcinogenesis

Lehoux

D’Abramo

Archambault³

2009

Public Health Genomics

102

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Approximately 20% of all cancers are associated with infectious agents. Among them, human papillomaviruses (HPVs) are very common and are now recognized as the etiological agent of cervical cancer, the second most common cancer in women worldwide, and they are increasingly linked with other forms of dysplasia. Carcinogenesis is a complex and multistep process requiring the acquisition of several genetic and/or epigenetic alterations. HPV-induced neoplasia, however, is in part mediated by the intrinsic functions of the viral proteins. In order to replicate its genome, HPV modulates the cell cycle, while deploying mechanisms to escape the host immune response, cellular senescence and apoptosis. As such, HPV infection leads directly and indirectly to genomic instability, further favouring transforming genetic events and progression to malignancy. This review aims to summarize our current understanding of the molecular mechanisms exploited by HPV to induce neoplasia, with an emphasis on the role of the 2 viral oncoproteins E6 and E7. Greater understanding of the role of HPV proteins in these processes will ultimately aid in the development of antiviral therapies, as well as unravel general mechanisms of oncogenesis.

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Regulation of Telomerase by Human Papillomaviruses

Cited by 3 publications

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Cell-Restricted Immortalization by Human Papillomavirus Correlates with Telomerase Activation and Engagement of the hTERT Promoter by Myc

Cell-Restricted Immortalization by Human Papillomavirus Correlates with Telomerase Activation and Engagement of the hTERT Promoter by Myc

HPV E6, E6AP and Cervical Cancer

Molecular Mechanisms of Human Papillomavirus-Induced Carcinogenesis

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