Human papillomavirus E2 protein associates with nuclear receptors to stimulate nuclear receptor- and E2-dependent transcriptional activations in human cervical carcinoma cells

Wu, Meng-Hsun; Chan, James; Liu, Pei-Yao; Liu, Shuting; Huang, Shih‐Ming

doi:10.1016/j.biocel.2006.09.008

Cited by 38 publications

(23 citation statements)

References 52 publications

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“…In addition, previous in vitro studies have clearly demonstrated that HR-HPVs E2, E6, and E7 proteins were able to directly interact with some NRs such as ER and AR with a secondary loss of normal growth control by steroid hormones (6)(7)(8). E6 and E7 oncoproteins may also both directly bind some NRs and serve as their cofactors.…”

Section: Ar In Cin and Cervical Carcinomamentioning

confidence: 93%

“…E6 and E7 oncoproteins may also both directly bind some NRs and serve as their cofactors. Others studies suggest that the NR coactivator function of HPV E2 proteins might be mediated through physical and functional interactions with not only NRs but also the NR coactivators ERIP1 (glucocorticoid receptorinteracting protein 1) and ZAC1 (zinc-finger protein, which regulates apoptosis and cell cycle arrest reciprocally regulating their transactivation activities (6)(7)(8). Lastly, it has been demonstrated that HPV status has varying effects on ER or PR expression in established cervical cancer cell lines; however, the effects on AR expression remain unknown (23)(24)(25)(26)(27).…”

Section: Ar In Cin and Cervical Carcinomamentioning

confidence: 99%

“…Recently, several authors have demonstrated in vivo that E6 and E7 proteins were able to directly interact with some nuclear receptors (NRs) and, particularly androgen receptor (AR), whether or not appropriate hormones were present (6)(7)(8). However, to the best of our knowledge, there are limited data in the literature pertaining to a potential expression of AR in cervical carcinogenesis.…”

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confidence: 93%

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Androgen Receptor Expression in Cervical Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix

Noël¹,

Bucella²,

Fayt³

et al. 2008

International Journal of Gynecological Pathology

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If in vitro studies have demonstrated a potential interaction between human papillomavirus (HPV) and androgen receptor (AR), their expression in vivo during cervical carcinogenesis remains unknown. To clarify the issue, we have tested by immunohistochemistry the expression status of AR in low-grade cervical intraepithelial neoplasia (LSIL-CIN1) (n=30), high-grade cervical intraepithelial neoplasia (HSIL-CIN2/3) (n=30), and invasive squamous cell carcinoma (ISCC) (n=13). All the patients with these lesions have got a corresponding liquid-based cytology and were proved to be HPV positive by using hybrid capture II methodology with probes against high-risk oncogenic HPVs (HR-HPVs). Thirty cases of normal exocervix epithelium served as controls. The evaluation of AR expression was performed by using H-score system, and an H-score >50 was considered positive. Androgen receptor expression was observed in 100% of normal epithelium (30/30) and LSIL (30/30), but only in 63% of HSIL (19/30) and 23% of ISCC (3/13). A statistically significant difference (P<0.05) concerning this expression was found between normal epithelium and HSIL or ISCC, between LSIL and HSIL or ISCC, and between HSIL and ISCC. To the best of our knowledge, this is the first study describing that the loss of AR expression is a frequent and common event in HSIL and ISCC resulting probably from complex interactions between HR-HPVs and these receptors. These data provide new insights concerning a potential role of androgen and AR in cervical carcinogenesis, which should be confirmed in furthers studies.

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Section: Ar In Cin and Cervical Carcinomamentioning

confidence: 93%

Section: Ar In Cin and Cervical Carcinomamentioning

confidence: 99%

mentioning

confidence: 93%

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Androgen Receptor Expression in Cervical Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix

Noël¹,

Bucella²,

Fayt³

et al. 2008

International Journal of Gynecological Pathology

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“…HeLa, HeLa/vector, and HeLa/p53 shRNA cells were grown in DMEM supplemented with 10% charcoal/dextran-treated fetal bovine serum as described previously (29). Transient transfections and luciferase assays were done in 24-well culture dishes as described previously (50).…”

Section: Cell Culture and Transient Transfection Assaysmentioning

confidence: 99%

Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells

Liu

Chan

Lin

et al. 2008

Molecular Cancer Research

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Zac1 is a novel seven -zinc finger protein which possesses the ability to bind specifically to GC-rich DNA elements. Zac1 not only promotes apoptosis and cell cycle arrest but also acts as a transcriptional cofactor for p53 and a number of nuclear receptors. Our previous study indicated that the enhancement of p53 activity by Zac1 is much more pronounced in HeLa cells compared with other cell lines tested. This phenomenon might be due to the coactivator effect of Zac1 on p53 and the ability of Zac1 to reverse E6 inhibition of p53. In the present study, we showed that Zac1 acted synergistically with either p53 or a histone deacetylase inhibitor, trichostatin A, to enhance p21 WAF1/Cip1 promoter activity. We showed that Zac1 physically interacted with some nuclear receptor corepressors such as histone deacetylase 1 (HDAC1) and mSin3a, and the induction of p21 WAF1/Cip1 gene and protein by Zac1 was suppressed by either overexpressing HDAC1 or its deacetylase-dead mutant. In addition, our data suggest that trichostatin A -induced p21 WAF1/Cip1 protein expression might be mediated through a p53-independent and HDAC deacetylaseindependent pathway. Taken together, our data suggest that Zac1 might be involved in regulating the p21 WAF1/Cip1 gene and protein expression through its protein-protein interaction with p53 and HDAC1 in HeLa cells.

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“…The TAD of E2 interacts with numerous viral and cellular proteins, including viral E1 protein, TFIIB, CHIR1, Brd4, NAP-1, p300/CBP, p/CAF, GR, and Tax1BP1 (23,26,29,33,39,46,47,49). Previous studies have reported that E2 proteins exhibit short half-lives due to degradation by the ubiquitin/proteasome pathway (3,38).…”

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confidence: 99%

NRIP, a Novel Calmodulin Binding Protein, Activates Calcineurin To Dephosphorylate Human Papillomavirus E2 Protein

Chang

Tsao

Lin

et al. 2011

J Virol

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Human papillomaviruses (HPVs) are small, doublestranded DNA viruses that infect squamous epithelial cells and have been strongly implicated in the development of human cervical cancer, which is the second most common cancer worldwide and the leading cause of death from cancer among women in developing countries (32,35,52). HPV E2 is a ϳ40-kDa nuclear protein that binds DNA and is a prototypical transcription factor with an N-terminal transcriptional activation domain (TAD) and a C-terminal DNA binding domain (DBD) separated by a hinge region (HR) (11). The E2 protein is an important regulator of elements of the viral life cycle such as viral transcription, viral DNA replication, and viral genome maintenance (11,30,31). To regulate viral transcription, HPV E2 can serve as either activator or repressor of transcription, depending upon the context of E2 binding sites within the promoter region. There are four E2 binding sites within the HPV long control region (LCR). The binding of E2 to the promoter-distal sites within the LCR could activate HPV transcription. When HPV E2 protein binds to the promoter-proximal sites, it functions as a transcription repressor (42) by preventing Sp1 and TFIID/TBP from binding to their cognate sequences, thereby inhibiting assembly of the transcription initiation complex.It is inconceivable that E2 can achieve its multiple functions without interacting with other proteins, and several E2-interaction proteins have already been reported. The TAD of E2 interacts with numerous viral and cellular proteins, including viral E1 protein, TFIIB, CHIR1, Brd4, NAP-1, p300/CBP, p/CAF, GR, and Tax1BP1 (23,26,29,33,39,46,47,49). Previous studies have reported that E2 proteins exhibit short half-lives due to degradation by the ubiquitin/proteasome pathway (3, 38). The TAD of E2 protein is highly conserved between papillomavirus groups and widely reported to be essential for ubiquitination and degradation by the proteasome. The C-terminal domain of E2 (such as BPV E2R) has a longer half-life due to the fact that it is not a good substrate for the ubiquitin-proteasome machinery (15). Several recently reported E2 interacting proteins bind to the TAD of E2 and contribute to E2 protein stability, such as Brd4 (8, 24, 51), Skp2 (4), and Tax1BP1 (46), but the mechanisms are still unclear. Moreover, mutational analysis in vitro has shown that the phosphorylation of BPV-1 E2 shortens the half-life of the protein (37) although the detailed mechanism of how E2 phosphorylation leads to protein degradation remains unclear.We previously identified a novel gene and named the protein nuclear receptor interaction protein (NRIP) (GenBank accession numbers AY766164 and AAX09330). The NRIP protein is composed of 860 amino acids and seven WD40 domains (43). NRIP acts to upregulate androgen receptor (AR) and glucocorticoid receptor (GR)-driven transcriptional activity of the native mouse mammary tumor virus (MMTV) promoter. Knockdown of NRIP expression can decrease the growth rate of various cells, implying that NRIP mig...

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Human papillomavirus E2 protein associates with nuclear receptors to stimulate nuclear receptor- and E2-dependent transcriptional activations in human cervical carcinoma cells

Cited by 38 publications

References 52 publications

Androgen Receptor Expression in Cervical Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix

Androgen Receptor Expression in Cervical Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix

Modulation of the Cyclin-Dependent Kinase Inhibitor p21WAF1/Cip1 Gene by Zac1 through the Antagonistic Regulators p53 and Histone Deacetylase 1 in HeLa Cells

NRIP, a Novel Calmodulin Binding Protein, Activates Calcineurin To Dephosphorylate Human Papillomavirus E2 Protein

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