scholarly journals Molecular simulation oF MDM2 and E6AP proteins as P53 regulator in cervical cancer

2020 ◽  
Vol 10 (4) ◽  
pp. 5875-5879
Keyword(s):  
Cervical Cancer ◽  
Free Energy ◽  
Molecular Docking ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
Transactivation Domain ◽  
Mdm2 Protein ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
Cervical Area

Cervical cancer is a type of cancer characterized by abnormal cell growth in the cervical area. One of the main events that happen during tumorigenesis is the inactivation or degradation of the genome guardian, P53. Under normal circumstances, P53 is regulated by MDM2 protein. MDM2 can transfer ubiquitin to the transactivation domain of P53, targeting it for degradation by proteasomes. However, in the presence of HPV, HPV-E6 can utilize cellular E6AP to perform P53 degradation through the ubiquitin ligase mechanism. We validated both interactions through molecular docking in ClusPro. We also checked their normalized expression level in The Cancer Genomic Atlas (TCGA) using TCGA-Assembler. We found out both interactions are highly likely due to the spontaneity of the reaction indicated by the low free energy. MDM2 is overexpressed in cervical cancer cells, but E6AP expression is relatively constant. This indicates that the MDM2-mediated pathway is still sustained in cervical cancer cells. But since E6AP-mediated pathway is finally activated due to the presence of HPV-E6, both pathways may happen simultaneously. Further research is needed to confirm both pathways existence in cervical cancer cells and how they may coincide and affect each other.

Inhibition of tumorigenicity of cervical cancer cells in nude mice by HPV e6-e7 anti-sense RNA

1992 ◽  
Vol 51 (5) ◽  
pp. 831-834 ◽  
Author(s):  
Magnus von Knebel Doeberitz ◽  
Claudia Rittmüller ◽  
Harald Zur Hausen ◽  
Matthias dürst
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Nude Mice ◽  
Hpv E6 ◽  
Cervical Cancer Cells

scholarly journals E6-mediated activation of JNK drives EGFR signalling to promote proliferation and viral oncoprotein expression in cervical cancer

2020 ◽  
Author(s):  
Ethan L. Morgan ◽  
James A. Scarth ◽  
Molly R. Patterson ◽  
Christopher W. Wasson ◽  
Georgia C. Hemingway ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Human Papillomaviruses ◽  
Signalling Pathway ◽  
Viral Oncoprotein ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7 ◽  
Novel Therapeutic

AbstractHuman papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

Methyl jasmonate reduces the survival of cervical cancer cells and downregulates HPV E6 and E7, and survivin

2012 ◽  
Vol 319 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Elad Milrot ◽  
Anna Jackman ◽  
Tatiana Kniazhanski ◽  
Pinhas Gonen ◽  
Eliezer Flescher ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Methyl Jasmonate ◽  
Cancer Cells ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7

CD71+ Population Enriched by HPV-E6 Protein Promotes Cancer Aggressiveness and Radioresistance in Cervical Cancer Cells

2019 ◽  
Vol 17 (9) ◽  
pp. 1867-1880 ◽  
Author(s):  
Thomas Ho-Yin Leung ◽  
Hermit Wai-Man Tang ◽  
Michelle Kwan-Yee Siu ◽  
David Wai Chan ◽  
Karen Kar-Loen Chan ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Hpv E6 ◽  
Cancer Aggressiveness ◽  
Cervical Cancer Cells ◽  
E6 Protein

scholarly journals Expression of the Long Noncoding RNA DINO in Human Papillomavirus-Positive Cervical Cancer Cells Reactivates the Dormant TP53 Tumor Suppressor through ATM/CHK2 Signaling

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Surendra Sharma ◽  
Karl Munger
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Tumor Suppressor ◽  
Cancer Cells ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Wild Type ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
Transcriptional Target

ABSTRACT Tumor cells overcome the cytostatic and cytotoxic restraints of TP53 tumor suppressor signaling through a variety of mechanisms. High-risk human papillomavirus (HPV)-positive tumor cells retain wild-type TP53 because the HPV E6/UBE3A ubiquitin ligase complex targets TP53 for proteasomal degradation. While restoration of TP53 in tumor cells holds great promise for cancer therapy, attempts to functionally restore the dormant TP53 tumor suppressor in HPV-positive cancer cells by inhibiting the HPV E6/UBE3A ubiquitin ligase complex have not yet been successful. The damage-induced long noncoding RNA, DINO (DINOL), is a TP53 transcriptional target that has been reported to bind to and stabilize TP53, thereby amplifying TP53 signaling. We show that HPV-positive cervical carcinoma cells contain low levels of DINO because of HPV E6/UBE3A-mediated TP53 degradation. Acute DINO expression overrides HPV16 E6/UBE3A-mediated TP53 degradation, causing TP53 stabilization and increased expression of TP53 transcriptional target genes. This causes a marked sensitization to chemotherapy agents and renders cells vulnerable to metabolic stress. Acute DINO expression in HPV-positive cervical cancer cells induces hallmarks of DNA damage response signaling, and TP53 activation involves ATM/CHK2 signaling. DINO upregulation in response to DNA damage is independent of ATM/CHK2 and can occur in cancer cells that express mutant TP53. IMPORTANCE Functional restoration of the TP53 tumor suppressor holds great promise for anticancer therapy. Current strategies are focused on modulating TP53 regulatory proteins. Long noncoding RNAs (lncRNAs) have emerged as important regulators of TP53 as well as modulators of downstream tumor-suppressive transcriptional responses. Unlike many other cancer types, human papillomavirus (HPV)-positive cancer cells retain wild-type TP53 that is rendered dysfunctional by the viral E6 protein. We show that acute expression of the damage-induced long noncoding RNA, DINO, a known TP53 transcriptional target and functional modulator, causes TP53 reactivation in HPV-positive cervical cancer cells. This causes increased vulnerability to standard chemotherapeutics as well as biguanide compounds that cause metabolic stress. Hence, strategies that target DINO may be useful for restoring TP53 tumor suppressor activity in HPV-positive cancers and other tumor types that retain wild-type TP53.

scholarly journals Leukemia Inhibitory Factor Downregulates Human Papillomavirus-16 Oncogene Expression and Inhibits the Proliferation of Cervical Carcinoma Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Joseph M. Bay ◽  
Bruce K. Patterson ◽  
Nelson N. H. Teng
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
Cancer Cells ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Human Papillomavirus 16 ◽  
Oncogene Expression ◽  
Hpv E6 ◽  
Cervical Cancer Cells ◽  
E6 And E7

The constitutive proliferation and resistance to differentiation and apoptosis of neoplastic cervical cells depend on sustained expression of human papillomavirus oncogenes. Inhibition of these oncogenes is a goal for the prevention of progression of HPV-induced neoplasias to cervical cancer. SiHa cervical cancer cells were transfected with an HPV-16 promoter reporter construct and treated with leukemia inhibitory factor (LIF), a human cytokine of the interleukin 6 superfamily. SiHa and CaSki cervical cancer cells were also assessed for proliferation by MTT precipitation, programmed cell death by flow cytometry, and HPV E6 and E7 expression by real-time PCR. LIF-treated cervical cancer cells showed significantly reduced HPV LCR activation, reduced levels of E6 and E7 mRNA, and reduced proliferation. We report the novel use of LIF to inhibit viral oncogene expression in cervical cancer cells, with concomitant reduction in proliferation suggesting re-engagement of cell-cycle regulation.

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