Expression of AP1 during cellular differentiation determines human papillomavirus E6/E7 expression in stratified epithelial cells.

Kyo, Satoru; Klumpp, David J.; Inoue, Masakí; Kanaya, Taro; Laimins, Laimonis A.

doi:10.1099/0022-1317-78-2-401

Cited by 69 publications

(56 citation statements)

References 30 publications

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“…The hypothesized chromatin-binding corepressor (Hou et al 2000) is now identified as Brd4. Second, the identification of AP-1, but not Sp1 and YY1 (data not shown), as a critical cellular transcription factor able to initiate transcription in vitro from silenced HPV chromatin, whose structure was first observed nearly 30 years ago by electron microscopy with viral samples obtained from human plantar warts (Favre et al 1977), directly demonstrates the involvement of AP-1 in HPV transcription and is consistent with genetic studies indicating the importance of AP-1-binding sites for E6/E7 gene expression in both differentiated and undifferentiated cell types, including keratinocytes and stratified epithelial tissues (Kyo et al 1997;Zhao et al 1997;and references therein). Third, the finding that acetylation on histones H3 and H4 remains unaltered following Brd4-mediated recruitment of E2 to the E6 promoter region indicates that acetylation on histone tails may also signal the recruitment of a sequence-specific transcriptional repressor whose chromatin targeting activity depends on the binding of a corepressor to acetylated chromatin.…”

Section: Discussionsupporting

confidence: 58%

Brd4 links chromatin targeting to HPV transcriptional silencing

et al. 2006

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The E2 protein encoded by human papillomaviruses (HPVs) inhibits expression of the viral E6 oncoprotein, which, in turn, regulates p53 target gene transcription. To identify cellular proteins involved in E2-mediated transcriptional repression, we isolated an E2 complex from human cells conditionally expressing HPV-11 E2. Surprisingly, the double bromodomain-containing protein Brd4, which is implicated in cell cycle control and viral genome segregation, was found associated with E2 and conferred on E2 the ability to inhibit AP-1-dependent HPV chromatin transcription in an E2-binding site- [Keywords: HPV; E2; AP-1; Brd4; chromatin transcription; gene silencing] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionsupporting

confidence: 58%

Brd4 links chromatin targeting to HPV transcriptional silencing

et al. 2006

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“…pGL3-EREpromoter was constructed by inserting head-in-tail tetramers of the ERE located at Ϫ2677 in the hTERT promoter, into the enhancer-less vector pGL3-promoter (18). pGL2-HPV31URR-luc vector is an HPV-31 enhancer and promoter-luciferase reporter containing the whole upstream regulatory region (URR) of HPV-31 cloned upstream of the luciferase gene in pGL2-Basic (27). These reporter plasmids were transiently transfected into cells for 24 h using LipofectAMINE Plus (Invitrogen) according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

Raloxifene Inhibits Estrogen-induced Up-regulation of Telomerase Activity in a Human Breast Cancer Cell Line

Koyama

Ohmichi

Takahashi

et al. 2003

Journal of Biological Chemistry

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The mechanism by which raloxifene acts in the chemoprevention of breast cancer remains unclear. Because telomerase activity is involved in estrogen-induced carcinogenesis, we examined the effect of raloxifene on estrogen-induced up-regulation of telomerase activity in MCF-7 human breast cancer cell line. Raloxifene inhibited the induction of cell growth and telomerase activity by 17␤-estradiol (E2). Raloxifene inhibited the E2-induced expression of the human telomerase catalytic subunit (hTERT), and transient expression assays using luciferase reporter plasmids containing various fragments of the hTERT promoter showed that the estrogen-responsive element appeared to be partially responsible for the action of raloxifene. E2 induced the phosphorylation of Akt, and pretreatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, attenuated the E2-induced increases of the telomerase activity and hTERT promoter activity. Raloxifene inhibited the E2-induced Akt phosphorylation. In addition, raloxifene also inhibited the E2-induced hTERT expression via the PI3K/Akt/NFB cascade. Moreover, raloxifene also inhibited the E2-induced phosphorylation of hTERT, association of NFB with hTERT, and nuclear accumulation of hTERT. These results show that raloxifene inhibited the E2-induced up-regulation of telomerase activity not only by transcriptional regulation of hTERT via an estrogenresponsive element-dependent mechanism and the PI3K/Akt/NFB cascade but also by post-translational regulation via phosphorylation of hTERT and association with NFB.

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“…Whether the virus reactivates S phase in a terminally differentiated, postmitotic cell or keeps active the cell cycle of a differentiating cell is unclear. Indeed, the phenomenon is variably described as S phase reentry in postmitotic, differentiated cells (Jian et al, 1998;Chien et al, 2002), maintenance of cells in a proliferative state in the course of differentiation (Kyo et al, 1997;Nguyen et al, 2002) or, perhaps most appropriately, left undecided (Jones et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

HPV E7 expression in skeletal muscle cells distinguishes initiation of the postmitotic state from its maintenance

2003

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The E7 oncogene is an essential tool used by papillomaviruses to interfere with the cell cycle and cellular differentiation. We investigated the effects of E7 expression on both cellular functions in skeletal muscle cells, a terminally differentiating system. When expressed in myoblasts, E7 impaired differentiation only partially, but allowed continuation of DNA synthesis during and after differentiation. Surprisingly, E7 expression in terminally differentiated myotubes could not reactivate DNA synthesis even though the oncogene bound the retinoblastoma protein, reduced its levels, and increased E2F transcriptional activity. Despite the high cyclin E protein levels induced by E7, the myotubes remained devoid of cyclin E-associated kinase activity. Enforcement of such activity in the presence of E7 brought myotubes into S phase. These results show that E7, unlike other DNA tumor-virus oncogenes, cannot reactivate the cell cycle in postmitotic myotubes. In contrast, E7 allows significant differentiation to occur in the presence of persisting DNA synthesis. These observations distinguish E7 from other functionally related oncogenes and bear significance for the understanding of the natural life cycle of human papillomaviruses. The fact that E7 alone inhibits the initiation but not the maintenance of the postmitotic state indicates that the mechanisms underlying these two functions are at least partially distinct.

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Expression of AP1 during cellular differentiation determines human papillomavirus E6/E7 expression in stratified epithelial cells.

Cited by 69 publications

References 30 publications

Brd4 links chromatin targeting to HPV transcriptional silencing

Brd4 links chromatin targeting to HPV transcriptional silencing

Raloxifene Inhibits Estrogen-induced Up-regulation of Telomerase Activity in a Human Breast Cancer Cell Line

HPV E7 expression in skeletal muscle cells distinguishes initiation of the postmitotic state from its maintenance

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