Prediction of Human proteins having interactions with HPV16 proteins using virus and host sequence motifs.

Background: Human Papillomavirus (HPV) infection has been found to be the major cause of cancer of cervical region, in females. Genome of HPV codes for 6 functional proteins E1, E2, E4, E5, E6 and E7. These proteins play different roles in development of HPV infection and its progression towards cervical cancer. The interactions of HPV proteins with human DNA and proteins occurs in the presence of short linear peptide motifs on these proteins, have similar sequence to those found on proteins in human cells. Methods: After identification of human motifs in HPV proteins, by use of ELM resource, their counter domains were found from PROSITE. The proteins of human proteome containing these counter domains were predicted as the proteins having possibility of interactions with HPV proteins. Results: we predicted 9468 human proteins for having interactions with HPV proteins. Our predicted proteins were enriched with the host proteins having possibility of being interacted by HPV proteins. 10% of our predicted proteins were already reported to be affected by one or more HPV proteins. The list of predicated proteins can be utilized to find out the connectivity between the virus HPV and human host. It can also be used to determine the pathways involved in pathogenesis of HPV leading towards the cervical cancer Conclusion: The list of predicated proteins can be utilized to find out the connectivity between the virus HPV and human host. It can also be used to determine the pathways involved in pathogenesis of HPV leading towards the cervical cancer.

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Insights into the Dynamic Fluctuations of the Protein HPV16 E1 and Identification of Motifs by Using Elastic Network Modeling

Protein and Peptide Letters ◽

10.2174/0929866528666210415114858 ◽

2021 ◽

Vol 28 ◽

Author(s):

Rabbiah Malik ◽

Sahar Fazal

Keyword(s):

Drug Targets ◽

Network Models ◽

Hpv Infection ◽

Elastic Network ◽

Conserved Sequence ◽

Linear Peptide ◽

Peptide Motifs ◽

E1 Protein ◽

Human Proteins ◽

Viral Helicase

Background: Cancers of cervix, head and neck regions have been found to be associated with Human Papilloma Virus (HPV) infection. E1 protein makes an important papillomavirus replication factor. Among the ORFs of papillomaviruses, the most conserved sequence is that of the E1 ORF. It is the viral helicase with being a member of class of ATPases associated with diverse cellular activities (AAA+) helicases. The interactions of E1 with human DNA and proteins occurs in the presence of short linear peptide motifs on E1 identical to those on human proteins. Methods: Different Motifs were identified on HPV16 E1 by using ELMs. Elastic network models were generated by using 3D structures of E1. Their dynamic fluctuations were analyzed on the basis of B factors, correlation analysis and deformation energies. Results: 3 motifs were identified on E1 which can interact with Cdk and Cyclin domains of human proteins. 11 motifs identified on E1 have their CDs of Pkinase on human proteins. LIG_MYND_2 has been identified as involved in stabilizing interaction of E1 with Hsp40 and Hsp70. These motifs and amino acids comprising these motifs play a major role in maintaining interactions with human proteins, ultimately causing infections leading to cancers. Conclusion: Our study identified various motifs on E1 which interact with specific counter domains found in human proteins, already reported having the interactions with E1. We also validated the involvement of these specific motifs containing regions of E1 by modeling elastic networks of E1. These motif involving interactions could be used as drug targets.

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Computational analysis of domains vulnerable To HPV-16 E6 Oncoprotein and corresponding hot spot residues.

Protein and Peptide Letters ◽

10.2174/0929866527666200722134801 ◽

2020 ◽

Vol 27 ◽

Author(s):

Rabbiah Manzoor Malik ◽

Sahar Fazal ◽

Mohammad Amjad Kamal

Keyword(s):

Cervical Cancer ◽

Hot Spot ◽

Network Models ◽

Host Protein ◽

Hpv 16 ◽

Protein Protein Interaction ◽

Linear Peptide ◽

Peptide Motifs ◽

E6 Oncoprotein ◽

Human Proteins

Background: Human Papilloma Virus (HPV) is the primary cause of cancers in cervix, head and neck regions. Oncoprotein E6 of HPV-16, after infecting human body, alters host protein-protein interaction networks. E6 interacts with several proteins, causing the infection to progress into cervical cancer. The molecular basis for these interactions is the presence of short linear peptide motifs on E6 identical to those on human proteins. Methods: Motifs of LXXLL and E/DLLL/V-G after identification on E6, were analyzed for their dynamic fluctuations by use of elastic network models. Correlation analysis of amino acid residues of E6 was also performed in specific regions of motifs. Results: Arginine, Leucine, Glutamine, Threonine and Glutamic acid have been identified as hot spot residues of E6 which can subsequently provide a platform for drug designing and understanding of pathogenesis of cervical cancer. These amino acids play a significant role in stabilizing interactions with host proteins, ultimately causing infections and cancers. Conclusion: Our study validates the role of linear binding motifs of E6 of HPV in interacting with these proteins as an important event in the propagation of HPV in human cells and its transformation into cervical cancer. The study further predicts the domains of protein kinase and armadillo as part of the regions involved in the interaction of E6AP, Paxillin and TNF R1, with viral E6.

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A Comprehensive Review on Crosstalk of Human Papilloma Virus oncoproteins and developmental/self-renewal pathways during the pathogenesis of uterine cervical cancer

Current Molecular Medicine ◽

10.2174/1566524020666200925160015 ◽

2020 ◽

Vol 20 ◽

Author(s):

Afza Ahmad ◽

Irfan Ahmad Ansari

Keyword(s):

Cervical Cancer ◽

Human Papilloma Virus ◽

Epithelial Mesenchymal Transition ◽

Wnt Signaling Pathway ◽

Hpv Infection ◽

Uterine Cervical Cancer ◽

Self Renewal ◽

Papilloma Virus ◽

Mesenchymal Transition ◽

E6 And E7

: Cervical cancer, a cancer arising from the uterine cervix has been regarded as the fourth most frequent gynecological malignancy among females worldwide. Epidemiological reports have shown that uterine cervical cancer is a global health issue among womens of specially developing countries and consequently creates an economic and medical burden in the society. The main causative agent of cervical carcinoma is high risk human papilloma virus (HPV 16 and HPV 18). Molecular studies have revealed the expression two viral genes E6 and E7 after HPV infection in the epithelial cells of cervix. These gene products are known to inactivate the major tumor suppressors, p53 and retinoblastoma protein (pRB), respectively. Moreover, the role of self-renewal pathways such as Hedgehog, Notch and Wnt has also been linked with drug resistance in cancer cells and epithelial mesenchymal transition during metastasis in pathogenesis of cervical cancer. Although, the mechanism of interaction of HPV E6 and E7 with each and every component of above described developmental pathways is not elucidated yet, but preliminary reports of their crosstalk have begun to emerge. Understanding the interplay between these oncoproteins and developmental/self-renewal pathways is highly important in terms of designing new and targeted therapeutic approach against cervical cancer. Hence, this review cynosure the carcinogenesis of HPV with the brief description of its virology and also establishes the crosstalk between oncoproteins E6 & E7 and Hedgehog, Notch and Wnt signaling pathway.

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Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells

BioMed Research International ◽

10.1155/2014/612823 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 57

Author(s):

Zheng Hu ◽

Lan Yu ◽

Da Zhu ◽

Wencheng Ding ◽

Xiaoli Wang ◽

...

Keyword(s):

Cervical Cancer ◽

Growth Inhibition ◽

Cancer Cells ◽

Hpv Infection ◽

Hek293 Cells ◽

Guide Rna ◽

System A ◽

Cervical Cancer Cells ◽

E6 And E7 ◽

Human Cervical Cancer Cells

High-risk human papillomavirus (HR-HPV) has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR-) associated protein system (CRISPR/Cas system), a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA) guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.

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The Presence of HPV in Dental Calculus: It’s Role in Pathogenesis of Oral and Cervical Cancer

10.5772/intechopen.98347 ◽

2021 ◽

Author(s):

Sunardhi Widyaputra ◽

Natallia Pranata ◽

Ignatius Setiawan ◽

Jamas Ari Anggraini

Keyword(s):

Cervical Cancer ◽

Oral Cavity ◽

Human Cancer ◽

Heparan Sulphate ◽

Basal Layer ◽

Hpv Infection ◽

Dental Calculus ◽

Oral Cancers ◽

Proliferation Capacity ◽

E6 And E7

Human papillomavirus (HPV) infection accounts for approximately 5.2% of the worldwide human cancer burden. Molecular epidemiologic evidence clearly indicates that certain types of HPV are the principal cause of both cervical and oral cancers. Major oncoproteins E6 and E7 can inactivate p53 and pRB proteins because it happened genome instability and dysregulation host cell cycles. This virus is an epithelial tropism, vulnerable area mainly at the basal layer and epithelial stem cell, because it still has a high proliferation capacity, so it can support the replication of the virus. Virions bind initially to the glycosaminoglycan (GAG) chains of heparan sulphate proteoglycan (HSPG). More than 99% cervical cancer arise at the cervical transformation zone. In oral cavity, exposed areas of the basal layer will be very susceptible to HPV infection. The HPV presence in the oral area is considered as one of the etiologics of oral cancer in those who do not have bad habits such as smoking, betel chewing, or poor oral hygiene. Our study successfully identified HPV type 58 in dental calculus. Dental calculus, calcified oral plaque biofilm, has been shown to be an abundant, nearly ubiquitous, and long-term reservoir of the ancient oral microbiome, including bacteria, archaea, eukaryote, and viruses. During biomineral maturation process, several biological contents around the oral region should be trapped, including the exfoliated virus contained cells. Dental calculus is a promising source of HPV and carcinogens molecules in the oral cavity and could be used as a biomarker for early detection.

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PENGEMBANGAN ANTIVIRUS HUMAN PAPILLOMA VIRUS BERBASIS MOLEKUL KECIL

Majalah Kedokteran Andalas ◽

10.22338/mka.v37.i1.p58-63.2014 ◽

2015 ◽

Vol 37 (1) ◽

pp. 58

Author(s):

Dwi Wulandari ◽

T. Mirawati Sudiro

Keyword(s):

Life Cycle ◽

Development Strategy ◽

Viral Proteins ◽

Hpv Infection ◽

Host Proteins ◽

Papilloma Virus ◽

Screening Programs ◽

Protein Functions ◽

E6 And E7 ◽

Inhibitor Interaction

AbstrakSekalipun telah ada program skrining deteksi dini infeksi HPV maupun kanker servis sertaadanya dua vaksin yang telah berlisensi, sekarang ini belum ada obat antivirus yang efektif.Prospek pengembangan molekul kecil inhibitor sebagai antivirus HPV sangat menjanjikan.Modulasi interaksi diantara protein-protein virus atau protein virus dengan protein hospesmenjadi strategi dalam upaya pengembangan molekul inhibitor sebagai antiviral HPV. Halini didukung oleh kemajuan pengetahuan mengenai fungsi protein HPV yang terlibat dalamsiklus hidupnya diantaranya yaitu protein E1, E2, E6 dan E7. Beberapa kandidat antivirustelah ditemukan dan masih dalam penelitian lebih lanjut untuk mendapatkan senyawa turunandengan aktivitas yang lebih tinggi diantaranya asam bifenil sulfonasetat (inhibitor ATPase E1).Indandione dan repaglinide (inhibitor interaksi E1-E2) dan senyawa-senyawa lainnya.AbstractEventhough there has been screening programs for HPV infection and cervical canceras well as the two vaccines that have been licensed, currently there is no effective cure forHPV. The prospects of the development of small molecule inhibitors as HPV antiviral is verypromising. Development strategy was based on the modulation of interactions between viralproteins or viral proteins with host proteins. This is supported by the advances in knowledgeabout HPV’s protein functions involved in their life cycle such as E1, E2, E6 and E7 proteins.Some antiviral molecule candidates have been found and need further studies to obtainderivatives with higher activity including acid biphenyl sulfonasetat (inhibitor ATPase E1),Indandione & repaglinide (inhibitor interaction E1-E2), etc.

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Novel Antigenic Targets of HPV Therapeutic Vaccines

Vaccines ◽

10.3390/vaccines9111262 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1262

Author(s):

Ditte Rahbæk Boilesen ◽

Karen Nørgaard Nielsen ◽

Peter Johannes Holst

Keyword(s):

Cervical Cancer ◽

Head And Neck ◽

Cytotoxic T Cells ◽

Expression Patterns ◽

Hpv Infection ◽

Therapeutic Vaccines ◽

Screening Programs ◽

Associated Lesions ◽

E6 And E7 ◽

Hpv Oncoproteins

Human papillomavirus (HPV) infection is the cause of the majority of cervical cancers and head and neck cancers worldwide. Although prophylactic vaccines and cervical cancer screening programs have shown efficacy in preventing HPV-associated cervical cancer, cervical cancer is still a major cause of morbidity and mortality, especially in third world countries. Furthermore, head and neck cancer cases caused by HPV infection and associated mortality are increasing. The need for better therapy is clear, and therapeutic vaccination generating cytotoxic T cells against HPV proteins is a promising strategy. This review covers the current scene of HPV therapeutic vaccines in clinical development and discusses relevant considerations for the design of future HPV therapeutic vaccines and clinical trials, such as HPV protein expression patterns, immunogenicity, and exhaustion in relation to the different stages and types of HPV-associated lesions and cancers. Ultimately, while the majority of the HPV therapeutic vaccines currently in clinical testing target the two HPV oncoproteins E6 and E7, we suggest that there is a need to include more HPV antigens in future HPV therapeutic vaccines to increase efficacy and find that especially E1 and E2 could be promising novel targets.

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Cervical cancer and HPV infection: ongoing therapeutic research to counteract the action of E6 and E7 oncoproteins

Drug Discovery Today ◽

10.1016/j.drudis.2019.07.011 ◽

2019 ◽

Vol 24 (10) ◽

pp. 2044-2057 ◽

Cited By ~ 13

Author(s):

Ana M. Almeida ◽

João A. Queiroz ◽

Fani Sousa ◽

Ângela Sousa

Keyword(s):

Cervical Cancer ◽

Hpv Infection ◽

E6 And E7 Oncoproteins ◽

E6 And E7 ◽

Therapeutic Research

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Patogenesis Human Papillomavirus (HPV) pada Kanker Serviks

Jurnal Biotek Medisiana Indonesia ◽

10.22435/jbmi.v8i1.2580 ◽

2019 ◽

Vol 8 (1) ◽

pp. 23-32

Author(s):

Paulina Rosa Evriarti ◽

Andi Yasmon

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

High Risk ◽

Scientific Journal ◽

Basal Layer ◽

Hpv Infection ◽

Host Cells ◽

Translation System ◽

Replication Process ◽

E6 And E7

AbstractCervical cancer is the most common cancer among women in the world. The main cause of the development of cervical cancer is due to persistent infection of a high-risk type (HR) - Human Papillomavirus (HPV). The mechanisms of HPV in causing cervical cancer are discussed in this article that collected from current information published in a scientific journal. The main target of HPV infection is the basal layer of cervical epithelia and the virus could reach its target when there is a microabrasion of epithelial cells. The HPV binds to its specific receptor on the host cellular surface and followed by the entering virus into the cytoplasm through the endocytosis process. After successfully entering the cell, the virus will uncoat and begin the replication process by hijacking the transcription and translation system of host cells. E6 and E7 proteins play an important role in the inactivation of tumor suppressor proteins p53 and pRb, causing the cells to uncontrolled divide (immortal). If the immune response failed to interfere with the replication process and eliminates HPV-infected cells, the HPV infection will lead to cervical cancer. In conclusion, the mechanism of HPV causing cervical cancer is complex and involves important proteins of HPV. AbstrakKanker serviks merupakan kanker paling banyak kedua yang diderita oleh perempuan di dunia. Penyebab utama dari perkembangan kanker serviks yakni adanya infeksi yang persisten tipe high risk (HR) – Human Papillomavirus (HPV). Artikel ini disusun untuk mengetahui mekanisme HPV dalam menimbulkan kanker serviks. Uraian dan tulisan mengenai isi artikel ini diperoleh dengan melakukan beberapa studi literatur yang terkait dengan HPV dalam menyebabkan kanker serviks. HPV dalam perannya menimbulkan kanker serviks diawali dengan masuknya HPV ke dalam lapisan sel epitel pejamu karena adanya mikroabrasi atau luka kecil. Bila berhasil melakukan pelekatan pada sel epitel serviks melalui reseptornya, virus akan diendositosis dan masuk ke dalam sel. Setelah berhasil masuk sel, virus akan mengalami uncoating, kemudian virus akan memulai proses replikasinya dengan cara mengambil alih sistem transkripsi dan translasi sel pejamu. Protein E6 dan E7 berperan penting dalam hal ini karena adanya kedua protein tersebut menghalangi kerja dari protein supressor tumor p53 dan pRb sehingga sel menjadi imortal dan pembelahan sel menjadi tidak terkendali. Apabila proses ini terakumulasi tanpa berhasil dieliminasi oleh sistem imun, infeksi oleh virus HPV dapat menjadi persisten dan timbul suatu keganasan berupa kanker serviks. Dari paparan tersebut, dapat ditarik kesimpulan bahwa mekanisme HPV dalam menyebabkan kanker serviks merupakan mekanisme yang cukup kompleks dan melibatkan protein-protein penting yang ada dalam genom HPV.

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Association of Human Papillomavirus Infection and Inflammation in Cervical Cancer

Pathogens and Disease ◽

10.1093/femspd/ftz048 ◽

2019 ◽

Cited By ~ 7

Author(s):

Nima Hemmat ◽

Hossein Bannazadeh Baghi

Keyword(s):

Cervical Cancer ◽

Human Papillomavirus ◽

Chronic Inflammation ◽

Inflammatory Cytokines ◽

Tissue Injury ◽

Hpv Infection ◽

Papillomavirus Infection ◽

E6 And E7 ◽

Pg E2 ◽

Pro Inflammatory Cytokines

Abstract Human papillomavirus (HPV) associated cancers, and in particular cervical cancer, are considered to be directly stimulated by HPV oncogenes. Alternatively, these types of cancers could also be indirectly stimulated by HPV-induced chronic inflammations, which in turn are also caused by HPV oncogenes activity. Chronic inflammation is associated with repeated tissue injury and development of mutations in the vital tumor suppressor genes. Thus, it is important to understand that the persistent HPV infection and its associated chronic inflammation is responsible for the progression of HPV-induced cancers. HPV E5, E6, and E7 could upregulate the expression of cyclooxygenase (COX)-2 and prostaglandin (PG) E2 followed by the activation of the COX-PG pathway. This pathway is assumed to be the main cause of HPV-induced inflammation. Additionally, HPV oncogenes could have an impact on the upregulation of pro-inflammatory cytokines in HPV-positive patients. The upregulation of such cytokines accelerates the incidence of inflammation following HPV infection. Other factors such as microRNAs, which are involved in the inflammation pathways and aging, give rise to the increased level of pro-inflammatory cytokines and could also be responsible for the acceleration of HPV-induced inflammation and consequent cervical cancer. In this review, the exact roles of HPV oncogenes in the occurrence of inflammation in cervical tissue, and the effects of other factors in this event are evaluated.

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