Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A

Pim, David; Massimi, Paola; Dilworth, S. J.; Banks, Lawrence

doi:10.1038/sj.onc.1208935

Cited by 163 publications

(150 citation statements)

References 43 publications

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“…The degradation of MAGI-2 and MAGI-3 by E6 may, therefore, result in the abolishment of PTEN function resulting in the activation of Akt-mediated cell growth. In addition, HPV-16 E7 upregulates AKT activity in both Rb-dependent and -independent manner (Westbrook et al, 2002;Pim et al, 2005;Menges et al, 2006). Taken together, these results highlight the importance of interference with the PI3 kinase/Akt-mediated signalling pathway in HPV-induced tumourigenesis.…”

Section: Discussionmentioning

confidence: 71%

Increased phosphorylation of p70 S6 kinase is associated with HPV16 infection in cervical cancer and esophageal cancer

et al. 2007

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HPV16 E6 interacts with and degrades tumour suppressor protein TSC2 leading to the phosphorylation of p70 S6 kinase. We studied the association of S6 kinase phosphorylation and HPV16 infection in cervical cancer and esophageal cancer. Immunohistochemistry was used to assess phosphorylated S6 kinase (Thr 389) and phosphorylated S6 (Ser235/236) in 140 cervical cancer and 161 esophageal cancer specimens. Immunohistochemical staining for pS6 kinase and pS6 was significantly more frequent in the HPV16-infected cervical cancer specimens than the HPV16-negative specimens. In contrast, the expression of S6 kinase was similar in both HPV16-positive and -negative samples. The phosphorylation of Akt, the key regulator of S6 kinase, was also detected. Our analysis showed that Akt phosphorylation was unaffected by HPV16 infection. These results together with our previous study suggest that HPV16 modifies S6 kinase activation via mechanism, which activates S6 kinase downstream of Akt function.

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Section: Discussionmentioning

confidence: 71%

Increased phosphorylation of p70 S6 kinase is associated with HPV16 infection in cervical cancer and esophageal cancer

et al. 2007

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“…Disruption of PI3K/Akt signaling has been reported in the malignant progression caused by two well known transforming viruses, hepatitis B virus and human papilloma virus (32,37,48,52). The hepatitis B virus oncoprotein HBx and the human papilloma virus proteins E6 and E7 have been implicated in alterations of the cellular PI3K/Akt pathway (75,76). Further supporting its importance in cancer, several reports have shown that PI3K/Akt activation contributes to chemotherapeutic resistance of leukemias (15,53,77).…”

Section: Discussionmentioning

confidence: 94%

Role for Akt/Protein Kinase B and Activator Protein-1 in Cellular Proliferation Induced by the Human T-cell Leukemia Virus Type 1 Tax Oncoprotein

Péloponèse

Jeang

2006

Journal of Biological Chemistry

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Human T-cell leukemia virus type 1 is an oncogenic retrovirus etiologically causal of adult T-cell leukemia. The virus encodes a Tax oncoprotein, which functions in transcriptional regulation, cell cycle control, and transformation. Because adult T-cell leukemia is a highly virulent cancer that is resistant to numerous chemotherapeutic treatments, to understand better this disease it is important to comprehend how human T-cell leukemia virus type 1 promotes cellular growth and survival. Most of the existing data point to Tax activation of NF-B as important for cellular proliferation and transformation. We show here that Tax, in the absence of NF-B signaling, can activate activator protein-1 to promote cellular proliferation and survival. Tax is shown to activate activator protein-1 through the phosphatidylinositol 3-kinase/Akt pathway.Many of the molecular alterations associated with carcinogenesis occur in cell signaling pathways that regulate cell proliferation and differentiation. Human T-cell leukemia virus type 1 (HTLV-1) 2 is the etiological agent for adult T-cell leukemia (ATL), an aggressive human T-cell malignancy (1-4). The mechanisms of ATL leukemogenesis are not yet fully understood. However, viral protein expression early in infection probably plays a major role for disease development (5-7).HTLV-1 encodes a 40-kDa nuclear oncoprotein, Tax (8, 9). There is strong evidence, including results from transgenic mice, that Tax plays an important role in cellular transformation (10 -12). A current view is that cellular transformation by HTLV-1 is linked to the capacity of Tax to deregulate cellular signaling pathways (13)(14)(15)(16)(17)(18)(19), to disrupt the cell's genetic integrity (20 -22), and to perturb cellular gene expression in part through activation of transcription factors such as NF-B and activator protein-1 (AP-1) (17,23,24). Aberrant activation of these signal transducers and their downstream mediators can provoke uncontrolled cell growth and malignant transformation (14,15,17). HTLV-1 infection can also trigger a hyperinflammatory host response leading to connective tissue diseases, such as rheumatoid arthritis, tropical spastic paraparesis, and HTLV-associated myelopathy (25, 26).Akt or protein kinase B (Akt/PKB) is a serine/threonine protein kinase that functions as a regulator of cell survival and proliferation (27)(28)(29)(30)(31). Akt/PKB is activated by PI3K through site-specific phosphorylation. Full activation of Akt requires phosphorylation of Ser 473 (31,32), and the actual mechanism of activation remains somewhat controversial and is not completely understood. Some have suggested that Akt could be activated in a PI3K-independent manner (31, 32), but the physiological significance of these findings remains poorly established. Aktbinding proteins have also been reported to regulate Akt activity (29). For example, the carboxyl-terminal modulator protein inhibits signaling by direct binding to Akt, leading to reduced phosphorylation at its Ser 473 residue. By contrast, proteins like...

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“…Elevated mTOR activity has previously been implicated in replication of adenoviruses (38). Interestingly, E7 alone also up-regulates activating phosphorylation of PKB/AKT (39,40). It will be interesting to examine the role of mTOR in the viral productive lifecycle.…”

Section: Discussionmentioning

confidence: 98%

HPV-18 E6 mutants reveal p53 modulation of viral DNA amplification in organotypic cultures

Kho

Wang

Banerjee

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Human papillomaviruses (HPVs) amplify in differentiated strata of a squamous epithelium. The HPV E7 protein destabilizes the p130/retinoblastoma susceptibility protein family of tumor suppressors and reactivates S-phase reentry, thereby facilitating viral DNA amplification. The high-risk HPV E6 protein destabilizes the p53 tumor suppressor and many other host proteins. However, the critical E6 targets relevant to viral DNA amplification have not been identified, because functionally significant E6 mutants are not stably maintained in transfected cells. Using Cre-loxP recombination, which efficiently generates HPV genomic plasmids in transfected primary human keratinocytes, we have recapitulated a highly productive infection of HPV-18 in organotypic epithelial cultures. By using this system, we now report the characterization of four HPV-18 E6 mutations. An E6 null mutant accumulated high levels of p53 and amplified very poorly. p53 siRNA or ectopic WT E6 partially restored amplification, whereas three missense E6 mutations that did not effectively destabilize p53 complemented the null mutant poorly. Unexpectedly, in cis, two of the missense mutants amplified, albeit to a lower extent than the WT and only in cells with undetectable p53. These observations and others implicate p53 and additional host proteins in regulating viral DNA amplification and also suggest an inhibitory effect of E6 overexpression. We show that high levels of viral DNA amplification are critical for late protein expression and report several previously undescribed viral RNAs, including bicistronic transcripts predicted to encode E5 and L2 or an alternative form of E1^E4 and L1.human papillomavirus DNA amplification | trans complementation | HPV transcripts P apillomaviruses are small DNA viruses with a protein capsid harboring a double-stranded circular genome of ∼7,900 bp. Dozens of human papillomavirus (HPV) types are tropic for the anogenital tract (1). HPV-16 and -18 and closely related genotypes are high-risk (HR) types and at a low frequency, can cause cancers, in which the viral E6 and E7 oncogenes are invariably overexpressed. HPV-6 and -11 are low-risk (LR) types and induce benign anogenital warts and laryngeal papillomas (review in ref. 2). Typically, viral DNA is maintained as low copy nuclear plasmids in basal and parabasal keratinocytes, and vegetative amplification depends on squamous differentiation (review in ref.3). Because viral DNA replication requires the host DNA replication machinery, the role of the HPV E7 protein is to promote S-phase reentry in differentiated cells that have withdrawn from the cell cycle. It does so by destabilizing the p130 protein (4, 5), a pocket protein related to the retinoblastoma susceptibility protein, a major tumor suppressor. The HR but not the LR HPV E7 protein also destabilizes retinoblastoma susceptibility protein (6). Both HR and LR HPV E6 proteins inactivate the transcription regulatory activities of another major tumor suppressor, p53 (7-10), abrogating its control over cell cycle ar...

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Activation of the protein kinase B pathway by the HPV-16 E7 oncoprotein occurs through a mechanism involving interaction with PP2A

Cited by 163 publications

References 43 publications

Increased phosphorylation of p70 S6 kinase is associated with HPV16 infection in cervical cancer and esophageal cancer

Increased phosphorylation of p70 S6 kinase is associated with HPV16 infection in cervical cancer and esophageal cancer

Role for Akt/Protein Kinase B and Activator Protein-1 in Cellular Proliferation Induced by the Human T-cell Leukemia Virus Type 1 Tax Oncoprotein

HPV-18 E6 mutants reveal p53 modulation of viral DNA amplification in organotypic cultures

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