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HPV & Cervical Cancer: Mechanisms Brandy Wells Advanced Cell Biology II Spring 2008, Johns Hopkins University
Cervical Cancer Basics ,[object Object],[object Object],[object Object]
HPV is Necessary Cause  of Cervical Cancer  ,[object Object],[object Object],Bosch et al., 2002.
HPV is Epitheliotropic ,[object Object],[object Object],[object Object],[object Object],Human Papillomavirus model*
HPV Genome ,[object Object],[object Object],[object Object],[object Object],[object Object],Munoz et al. 2006.
HPV Classification:  Carcinogenic Risk ,[object Object],[object Object],[object Object],[object Object],[object Object],Furumoto et al., 2002. 16, 18, 45, 56 High Risk 31, 33, 35, 51, 52, 58 Intermediate Risk 60, 11, 42, 43, 44 Low Risk
Early Genes Hijack Cell Cycle Checkpoint ,[object Object],[object Object],[object Object],[object Object],[object Object]
E6 & E7 in  Cervical Cancer Progression Furumoto et al., 2002.
Consequences of the HPV Hijack ,[object Object],[object Object],[object Object],[object Object],[object Object]
High-Risk HPV Oncoproteins: E6 Hausen, 2000. (1) Band et al., 1990  (2) Werness et al., 1990 & Sheffner et al., 1993  (3) Werness et al., 1990 & Thomas, 1998  (4) White et al.,1994  (5) Kessis et al., 1996 & Havre et al., 1995  (6) Klingelhutz et al., 1996  (7) Ronco et al., 1998 (8) Banks et al., 1998 & 1999 (1) Cell immmortalization  (2) Binding of E6-associated protein results in degradation of specific host cell proteins [p53]  (3) Anti-apoptotic effect (4) Chromosomal destabilization  (5) Enhancement of foreign DNA integration & mutagenicity  (6) Activation of telomerase  (7) Blockade of interferon functions (8) Degradation of Bak protein Investigator E6 Identified Function
E6 is Pleiotropic ,[object Object],[object Object],HPV-16  E6  protein from SWISS-Model Repository  (P03126)
Significance of  HIF-1 α  Expression in Cervical Cancer ,[object Object],[object Object],[object Object]
Evidence of  HIF-1 α   Overexpression in Cervical Cancer ,[object Object],[object Object],[object Object],A B Invasive cervical cancer specimens exhibiting strong (A) & weak (B)  HIF-1 α  expression Birner et al., 2000
Candidate for  Anti-angiogenesis Therapy? ,[object Object],[object Object],[object Object],[object Object]
High-Risk HPV Oncoproteins: E7 Hausen, 2000. (1) Munger & Phelps, 1993 (2) Arroyo et al., 1993 & Zerfass et al., 1995  (3) Putthenveettil et al., 1996  (4) Jones et al., 1997 & Funk et al., 1997 (5) Kessis et al., 1996 & Reznikoff et al., 1996  (6) Oda et al., 1999 (7) Dyson et al., 1989, 1992. (1) Cell immmortalization  (2) Activation of cyclins E & A (3) Induction of apoptosis (4) Inhibition of cyclin-dependent kinase inhibitors (5) Enhancement of foreign DNA integration & mutagenicity  (6) Degradation of Blk tyrosine kinase (7) Inactivation of retinoblastoma protein-related pocket proteins Investigator E7 Identified Function
E7 is Pleiotropic ,[object Object],[object Object],HPV-1a  E7  protein from SWISS-Model Repository  (P06465)
IRF-1  Deactivation by  E7 ,[object Object],[object Object],[object Object],[object Object],Normal role of IRF-1 in tumor suppressor mechanism
Mechanism of  IRF-1  Inactivation ,[object Object],[object Object],[object Object],Park et al., 2000.
Notch1  Signaling Pathway in  HPV-Cervical Cancer ,[object Object],[object Object],Talora et al., 2002.
Consequences of  Notch1  Downregulation ,[object Object],[object Object],[object Object],A/B:  Notch1  staining in normal cervical biopsy Notch1  staining in CIN lesion (C) & invasive cervical cancer (D) biopsies Talora et al., 2002.
E6 & E7 Integrate into Host Genome ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Carcinogenesis by HPV Bosch et al. 2002.
Preventative Intervention ,[object Object],[object Object],[object Object],[object Object]
CIN: Pre-Cancerous Warning ,[object Object],[object Object],[object Object],[object Object],[object Object]
Stages of CIN ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]
Stages of CIN: Histology NORMAL CIN I CIN II CIN III Furumoto et al., 2002.
Cervical Cancer Cofactors ,[object Object],[object Object],[object Object],[object Object],[object Object]
HPV Vaccination ,[object Object],[object Object],[object Object],[object Object],[object Object]
Treatment Options ,[object Object],[object Object],[object Object]
References ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

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HPV and Cervical Cancer: Mechanisms

  • 1. HPV & Cervical Cancer: Mechanisms Brandy Wells Advanced Cell Biology II Spring 2008, Johns Hopkins University
  • 2.
  • 3.
  • 4.
  • 5.
  • 6.
  • 7.
  • 8. E6 & E7 in Cervical Cancer Progression Furumoto et al., 2002.
  • 9.
  • 10. High-Risk HPV Oncoproteins: E6 Hausen, 2000. (1) Band et al., 1990 (2) Werness et al., 1990 & Sheffner et al., 1993 (3) Werness et al., 1990 & Thomas, 1998 (4) White et al.,1994 (5) Kessis et al., 1996 & Havre et al., 1995 (6) Klingelhutz et al., 1996 (7) Ronco et al., 1998 (8) Banks et al., 1998 & 1999 (1) Cell immmortalization (2) Binding of E6-associated protein results in degradation of specific host cell proteins [p53] (3) Anti-apoptotic effect (4) Chromosomal destabilization (5) Enhancement of foreign DNA integration & mutagenicity (6) Activation of telomerase (7) Blockade of interferon functions (8) Degradation of Bak protein Investigator E6 Identified Function
  • 11.
  • 12.
  • 13.
  • 14.
  • 15. High-Risk HPV Oncoproteins: E7 Hausen, 2000. (1) Munger & Phelps, 1993 (2) Arroyo et al., 1993 & Zerfass et al., 1995 (3) Putthenveettil et al., 1996 (4) Jones et al., 1997 & Funk et al., 1997 (5) Kessis et al., 1996 & Reznikoff et al., 1996 (6) Oda et al., 1999 (7) Dyson et al., 1989, 1992. (1) Cell immmortalization (2) Activation of cyclins E & A (3) Induction of apoptosis (4) Inhibition of cyclin-dependent kinase inhibitors (5) Enhancement of foreign DNA integration & mutagenicity (6) Degradation of Blk tyrosine kinase (7) Inactivation of retinoblastoma protein-related pocket proteins Investigator E7 Identified Function
  • 16.
  • 17.
  • 18.
  • 19.
  • 20.
  • 21.
  • 22. Carcinogenesis by HPV Bosch et al. 2002.
  • 23.
  • 24.
  • 25.
  • 26. Stages of CIN: Histology NORMAL CIN I CIN II CIN III Furumoto et al., 2002.
  • 27.
  • 28.
  • 29.
  • 30.