Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses

Nakamura, Mitsuhiro; Bodily, Jason M.; Beglin, Melanie; Kyo, Satoru; Inoue, Masakí; Laimins, Laimonis A.

doi:10.1016/j.virol.2009.02.036

Cited by 106 publications

(107 citation statements)

References 54 publications

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“…Northern analysis of miR-203 was performed on total RNA isolated using RNA Stat-60 as previously described (38). Briefly, 15 g of total RNA was separated on a small 17% SDS gel containing 7 M urea for 2 h at 180 V in 0.5ϫ Tris-borate-EDTA (TBE) buffer.…”

Section: Methodsmentioning

confidence: 99%

Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins

Melar-New

Laimins

2010

J Virol

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154

140

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Human papillomaviruses (HPV) link their life cycles to epithelial differentiation and induce productive replication of viral DNA in suprabasal cells. Viral-DNA amplification requires cells to remain active in the cell cycle upon differentiation. This is in contrast to normal cells, which lose proliferative capability upon differentiation. One factor that negatively regulates proliferative capability upon differentiation is microRNA 203 (miR-203), which is expressed primarily in suprabasal epithelial cells. Although HPVs do not encode their own microRNAs (miRNAs), they modulate expression of cellular miRNAs to regulate the activities of cellular proteins. We show that the HPV E7 protein downregulates miR-203 expression upon differentiation, which may occur through the mitogen-activated protein (MAP) kinase/protein kinase C (PKC) pathway. One target of miR-203 is the p63 family of transcription factors, and we demonstrate that HPV-positive cells maintain significantly higher levels of these factors upon differentiation than do normal keratinocytes. Several downstream targets of p63, CARM-1, p21, and Bax, were also increased in E7-expressing cells, and their levels were inversely correlated with amounts of miR-203. Introduction of expression vectors for miR-203 into keratinocytes that stably maintain HPV episomes resulted in short-term elevation of HPV genome copy numbers, but these were rapidly lost upon subsequent passage. When HPV-positive cells expressing high levels of miR-203 were induced to differentiate in methylcellulose, impaired genome amplification was observed. We conclude that high levels of miR-203 are inhibitory to HPV amplification and that HPV proteins act to suppress expression of this microRNA to allow productive replication in differentiating cells.

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Section: Methodsmentioning

confidence: 99%

Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins

Melar-New

Laimins

2010

J Virol

Self Cite

154

140

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“…Whole-cell extracts were prepared and subjected to SDS-PAGE and Western blotting as described previously (4,40). Antibodies used were glyceraldehyde-3-phosphate dehydrogenase (GAPDH; sc-47724; Santa Cruz), pRb (9309; Cell Signaling), cyclin A (C4710; Sigma), and E7 (28-0006; Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

The E7 Open Reading Frame Acts in cis and in trans To Mediate Differentiation-Dependent Activities in the Human Papillomavirus Type 16 Life Cycle

Bodily

Mehta

Cruz

et al. 2011

J Virol

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Human papillomaviruses (HPVs) are the causative agents of several important genital and other mucosal cancers. The HPV16 E7 gene encodes a viral oncogene that is necessary for the continued growth of cancer cells, but its role in the normal, differentiation-dependent life cycle of the virus is not fully understood. The function of E7 in the viral life cycle was examined using a series of mutations of E7 created in the context of the complete HPV16 genome. The effect of these E7 mutations on key events of the viral life cycle, including immortalization, episomal maintenance, late promoter activation, and infectious virion synthesis, was examined. Our studies show that the pRb binding domain is indispensable for early viral activities, whereas the C-terminal zinc finger domain contributed primarily to very late events. Mutations of the casein kinase II phosphorylation site caused a complex phenotype involving both the function of E7 protein and a cis element necessary for the activation of the late promoter, identifying for the first time a promoter element important for late promoter function in the context of the viral genome. All mutant genomes tested showed reduced viral titers following growth in organotypic raft cultures. These studies clarify the role of E7 as a regulator of late events in the differentiation-dependent HPV life cycle.

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“…Reappearance of HPV from latency even in the absence of definite immunosuppression is common, but most cases are probably benign. 71 In contrast to HPV infections that clear, the risk of cancer increases dramatically when infection becomes persistent. 17 This occurs due to the characteristics of the infection and the strategy adopted by the viruses to evade the defense mechanisms of the host, which becomes indifferent to the presence of the virus.…”

Section: Viral Persistence and Clearancementioning

confidence: 99%

Biology and natural history of human papillomavirus infection

Fernandes¹,

Araújo²,

Fernandes³

2013

OAJCT

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Human papillomavirus (HPV) is one of the most common causes of sexually transmitted diseases worldwide. It has been proposed that the great majority of women and men have been infected with HPV at least once during their lifetime. HPV infection is associated with a variety of clinical conditions, ranging from benign lesions to cervical cancer. In most cases, the infection is transient, where most of the individuals are healing, eliminating the virus without the presence of any clinical manifestation. Actually, more than 120 HPV types have been cataloged, of which approximately 40 can infect the mucosa of the anogenital tract and are collectively known as mucosal HPV, which are classified based on their oncogenic potential as either low-or high-risk HPV types. The low-risk HPV type causes benign hyperproliferative lesions or genital warts, with a very limited tendency for malignant progression, while the high-risk HPV type is strongly associated with premalignant and malignant cervical lesions. The HPV cycle initiates when the virus gains access to undifferentiated cells of the basement membrane of the squamous columnar junction epithelium of the ectocervix, after these regions are exposed to mechanical or chemical trauma. The basal cells in the transformation zone retain the ability to differentiate, a property required for virion production. Cervical infection with high-risk HPV typically lasts from 12 to 18 months and in most cases is cleared spontaneously. However, in some women the immune response is insufficient to eliminate the virus, resulting in a persistent, long-term infection that may progress to a malignant lesion. In this review, we discuss the biology and natural history of HPV infection and its association with cervical cancer.

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Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses

Cited by 106 publications

References 54 publications

Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins

Human Papillomaviruses Modulate Expression of MicroRNA 203 upon Epithelial Differentiation to Control Levels of p63 Proteins

The E7 Open Reading Frame Acts in cis and in trans To Mediate Differentiation-Dependent Activities in the Human Papillomavirus Type 16 Life Cycle

Biology and natural history of human papillomavirus infection

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