Human papillomavirus pathophysiology: Difference between revisions
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:growth.<ref name="pmid8221889">{{cite journal| author=Scheffner M, Huibregtse JM, Vierstra RD, Howley PM| title=The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. | journal=Cell | year= 1993 | volume= 75 | issue= 3 | pages= 495-505 | pmid=8221889 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8221889 }} </ref><ref name="pmid7671255">{{cite journal| author=Havre PA, Yuan J, Hedrick L, Cho KR, Glazer PM| title=p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. | journal=Cancer Res | year= 1995 | volume= 55 | issue= 19 | pages= 4420-4 | pmid=7671255 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7671255 }} </ref><ref name="pmid2157286">{{cite journal| author=Werness BA, Levine AJ, Howley PM| title=Association of human papillomavirus types 16 and 18 E6 proteins with p53. | journal=Science | year= 1990 | volume= 248 | issue= 4951 | pages= 76-9 | pmid=2157286 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2157286 }} </ref><ref name="pmid9426696">{{cite journal| author=Magal SS, Jackman A, Pei XF, Schlegel R, Sherman L| title=Induction of apoptosis in human keratinocytes containing mutated p53 alleles and its inhibition by both the E6 and E7 oncoproteins. | journal=Int J Cancer | year= 1998 | volume= 75 | issue= 1 | pages= 96-104 | pmid=9426696 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9426696 }} </ref><ref name="pmid8183918">{{cite journal| author=Demers GW, Foster SA, Halbert CL, Galloway DA| title=Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 10 | pages= 4382-6 | pmid=8183918 | doi= | pmc=43789 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8183918 }} </ref> | :growth.<ref name="pmid8221889">{{cite journal| author=Scheffner M, Huibregtse JM, Vierstra RD, Howley PM| title=The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. | journal=Cell | year= 1993 | volume= 75 | issue= 3 | pages= 495-505 | pmid=8221889 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8221889 }} </ref><ref name="pmid7671255">{{cite journal| author=Havre PA, Yuan J, Hedrick L, Cho KR, Glazer PM| title=p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. | journal=Cancer Res | year= 1995 | volume= 55 | issue= 19 | pages= 4420-4 | pmid=7671255 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7671255 }} </ref><ref name="pmid2157286">{{cite journal| author=Werness BA, Levine AJ, Howley PM| title=Association of human papillomavirus types 16 and 18 E6 proteins with p53. | journal=Science | year= 1990 | volume= 248 | issue= 4951 | pages= 76-9 | pmid=2157286 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2157286 }} </ref><ref name="pmid9426696">{{cite journal| author=Magal SS, Jackman A, Pei XF, Schlegel R, Sherman L| title=Induction of apoptosis in human keratinocytes containing mutated p53 alleles and its inhibition by both the E6 and E7 oncoproteins. | journal=Int J Cancer | year= 1998 | volume= 75 | issue= 1 | pages= 96-104 | pmid=9426696 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9426696 }} </ref><ref name="pmid8183918">{{cite journal| author=Demers GW, Foster SA, Halbert CL, Galloway DA| title=Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 10 | pages= 4382-6 | pmid=8183918 | doi= | pmc=43789 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8183918 }} </ref> | ||
*'''Inhibition of Rb protein''' | *'''Inhibition of Rb protein''' | ||
:Rb protein is negative regulator of cell growth. It binds E2F [[transcription factor]] which controls [[DNA replication]] and [[cyclin]] protein induced entering of cell into S phase of cell cycle. E7 protein binds Rb/E2F, releasing E2F from the inhibitory effect of Rb causing increased cyclin induced entry of cell into [[S phase]] of cell cycle, resulting in increased replication rate of cells accumulating mutations.<ref name=" | :Rb protein is negative regulator of cell growth. It binds E2F [[transcription factor]] which controls [[DNA replication]] and [[cyclin]] protein induced entering of cell into S phase of cell cycle. E7 protein binds Rb/E2F, releasing E2F from the inhibitory effect of Rb causing increased cyclin induced entry of cell into [[S phase]] of cell cycle, resulting in increased replication rate of cells accumulating mutations.<ref name="pmid8183918">{{cite journal| author=Demers GW, Foster SA, Halbert CL, Galloway DA| title=Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7. | journal=Proc Natl Acad Sci U S A | year= 1994 | volume= 91 | issue= 10 | pages= 4382-6 | pmid=8183918 | doi= | pmc=43789 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8183918 }} </ref><ref name="pmid1323816">{{cite journal| author=Pagano M, Dürst M, Joswig S, Draetta G, Jansen-Dürr P| title=Binding of the human E2F transcription factor to the retinoblastoma protein but not to cyclin A is abolished in HPV-16-immortalized cells. | journal=Oncogene | year= 1992 | volume= 7 | issue= 9 | pages= 1681-6 | pmid=1323816 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1323816 }} </ref><ref name="pmid8380917">{{cite journal| author=Tommasino M, Adamczewski JP, Carlotti F, Barth CF, Manetti R, Contorni M et al.| title=HPV16 E7 protein associates with the protein kinase p33CDK2 and cyclin A. | journal=Oncogene | year= 1993 | volume= 8 | issue= 1 | pages= 195-202 | pmid=8380917 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8380917 }} </ref><ref name="pmid10228159">{{cite journal| author=Brehm A, Nielsen SJ, Miska EA, McCance DJ, Reid JL, Bannister AJ et al.| title=The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth. | journal=EMBO J | year= 1999 | volume= 18 | issue= 9 | pages= 2449-58 | pmid=10228159 | doi=10.1093/emboj/18.9.2449 | pmc=1171327 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10228159 }} </ref> | ||
=== HPV-Induced Diseases === | === HPV-Induced Diseases === | ||
Revision as of 12:42, 14 October 2016
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Aysha Anwar, M.B.B.S[2]
Overview
Pathophysiology
Transmission
- Human papilloma virus is usually transmitted via the sexual route to the human host.
- Different types of HPV has a predilection for different types of epithelial tissue.
HPV life cycle
- HPV life cycle is linked to epithelial differentiation and maturation of host keratinocytes, with transcription of specific gene products at every level.
- HPV primarily infects basal cell layer of stratified squamous keratinised epithelium.
- Following transmission, the HPV uses the microabrasions to enter the basal stem cells via tissue specific heparan sulfate proteoglycans through clathrin-mediated endocytosis and/or caveolin-mediated endocytosis depending on the type of HPV.
- It than undergoes viral uncoating and viral DNA genome is than transported to nucleus maintaining a low copy number 10-200 viral genomes per cell (episome form)
- A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium.
- HPV uses host DNA replicative machinery to multiply as it lacks DNA polymerase activity.
- Specific viral genes are transcribed at every level of keratinocyte differention.
- Early proteins: E1, E2, E3, E4, E5, E6 and E7 proteins are synthesized primarily in middle layers, for reactivation of replication process in the differentiated cells.
- Late proteins: L1, L2 proteins are transcribed in the most superficial layers for virion assesmbly, release and reinfection, as they code for capsid proteins.
Pathogenesis of HPV induced cancers
The pathogenesis of HPV infection causing cancer is mainly linked to high risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). Following HPV proteins play a significant role in the development of cancers associated with HPV.[1]
E6 and E7 proteins
E6 and E7 protein products of HPV interact with two important cell cycle regulatory protiens, P53 and Rb proteins of host cell, causing unchecked cellular replication accumulating mutations leading to cancer.
- Inhibition of P53
- P53 protein is a cellular check point at G0/G1 to S phase of cell cycle and is also responsible for cell apoptosis for unrepaired DNA mutations. E6 protein binds P53 which results in degradation of P53, leaving cell without any check for mutations and unregulated cell.[2][3]
- growth.[4][5][6][7][8]
- Inhibition of Rb protein
- Rb protein is negative regulator of cell growth. It binds E2F transcription factor which controls DNA replication and cyclin protein induced entering of cell into S phase of cell cycle. E7 protein binds Rb/E2F, releasing E2F from the inhibitory effect of Rb causing increased cyclin induced entry of cell into S phase of cell cycle, resulting in increased replication rate of cells accumulating mutations.[8][9][10][11]
HPV-Induced Diseases
| Disease | HPV type |
|---|---|
| Common warts | 2, 7 |
| Plantar warts | 1, 2, 4 |
| Flat cutaneous warts | 3, 10 |
| Anogenital warts | 6, 11, 42, 43, 44, 55 and others |
| Genital malignancies | 16, 18, 31, 33, 35, 39, 45, 51 |
| Epidermodysplasia verruciformis | more than 15 types |
| Focal epithelial hyperplasia (oral) | 13, 32 |
| Oral papillomas | 6, 7, 11, 16, 32 |
References
- ↑ de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B; et al. (2010). "Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study". Lancet Oncol. 11 (11): 1048–56. doi:10.1016/S1470-2045(10)70230-8. PMID 20952254.
- ↑ Masuda H, Miller C, Koeffler HP, Battifora H, Cline MJ (1987). "Rearrangement of the p53 gene in human osteogenic sarcomas". Proc Natl Acad Sci U S A. 84 (21): 7716–9. PMC 299371. PMID 2823272.
- ↑ Hinds P, Finlay C, Levine AJ (1989). "Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation". J Virol. 63 (2): 739–46. PMC 247745. PMID 2642977.
- ↑ Scheffner M, Huibregtse JM, Vierstra RD, Howley PM (1993). "The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53". Cell. 75 (3): 495–505. PMID 8221889.
- ↑ Havre PA, Yuan J, Hedrick L, Cho KR, Glazer PM (1995). "p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells". Cancer Res. 55 (19): 4420–4. PMID 7671255.
- ↑ Werness BA, Levine AJ, Howley PM (1990). "Association of human papillomavirus types 16 and 18 E6 proteins with p53". Science. 248 (4951): 76–9. PMID 2157286.
- ↑ Magal SS, Jackman A, Pei XF, Schlegel R, Sherman L (1998). "Induction of apoptosis in human keratinocytes containing mutated p53 alleles and its inhibition by both the E6 and E7 oncoproteins". Int J Cancer. 75 (1): 96–104. PMID 9426696.
- ↑ 8.0 8.1 Demers GW, Foster SA, Halbert CL, Galloway DA (1994). "Growth arrest by induction of p53 in DNA damaged keratinocytes is bypassed by human papillomavirus 16 E7". Proc Natl Acad Sci U S A. 91 (10): 4382–6. PMC 43789. PMID 8183918.
- ↑ Pagano M, Dürst M, Joswig S, Draetta G, Jansen-Dürr P (1992). "Binding of the human E2F transcription factor to the retinoblastoma protein but not to cyclin A is abolished in HPV-16-immortalized cells". Oncogene. 7 (9): 1681–6. PMID 1323816.
- ↑ Tommasino M, Adamczewski JP, Carlotti F, Barth CF, Manetti R, Contorni M; et al. (1993). "HPV16 E7 protein associates with the protein kinase p33CDK2 and cyclin A." Oncogene. 8 (1): 195–202. PMID 8380917.
- ↑ Brehm A, Nielsen SJ, Miska EA, McCance DJ, Reid JL, Bannister AJ; et al. (1999). "The E7 oncoprotein associates with Mi2 and histone deacetylase activity to promote cell growth". EMBO J. 18 (9): 2449–58. doi:10.1093/emboj/18.9.2449. PMC 1171327. PMID 10228159.