JAX 15 minute talk

Transcript

1. Jordan Tyshia Mallory Katie Papillomaviruses:   Of  Mice  And  Men! Miranda Surendra REAL
2. Papillomaviruses Infect  squamous  epithelial  cells Cause  hyperplastic  lesions  (warts) Circular  8  kB dsDNA genomes One  coding  strand HPV16 7904bp E6 E7 E1 E2 E4 E5 L1 L2 LCR P97 P670 7904/1 1000 2000 3000 4000 5000 6000 7000 polyAE polyAL
3. Human  Papillomaviruses ~200  HPVs beta HPVs gamma HPVs cutaneous  warts? cutaneous  warts SCCs  in  “special”  patients ~5%  of  all  human  cancers >99%  of  cervical  carcinomas ~90%  anal  carcinomas ~40%  vulvar  and  vaginal  carcinomas ~20%  of  oral  cancers  (60%  OPSCC) alpha  HPVs “low-­‐risk”    – genital  warts “high-­‐risk”  – premalignant  lesions  (CIN)
4. Productive  Infection HPV Infection Productive   lesion Clearance/Regression HPV  infection
5. Productive  Infection HPV Infection Premalignant   lesion 1-­‐5  Years Clearance/Regression High-­‐risk  alpha  HPV  infection
6. Invasive   Cancer 1–40  Years LCR E6 E7 E1 L1 Non-­‐productive  Infection HPV  cancer:  a  rare  outcome  of  a  frequent   infection  and  not  part  of  viral  life  cycle Productive  Infection HPV Infection Premalignant   lesion 1-­‐5  Years HPV  carcinogenesis
7. HPV16  E6/E7  expressing  epithelial  cells  resemble  CINs HPV16  E6/E7  causes  cervical  cancer  in  transgenic  mice Cervical  cancer  cell  lines  are  addicted  to  E6/E7  expression LCR E6 E7 E1 L1 HPV  E6/E7
8. Small,  non-­‐enzymatic No  cellular  homologues No  specific  DNA  binding Associate  with  and  modify  cellular  protein  complexes -­‐ X29   -­‐ CXXC CXXC 1 151 E6 -­‐ X29   -­‐ CXXC CXXC LXCXE 1 98 E7 -­‐ X29   -­‐ CXXC CXXC HPV  E6/E7
9. Genomic Instability E6 E7 Cellular Immortalization TERT E6 Extended proliferation E6 UBE3A TP53 Aberrant proliferation E7 RB1/E2F CUL2 Figure 6. Therapeutic Targeting of the Hallmarks of Cancer Drugs that interfere with each of the acquired capabilities necessary for tumor growth and progression have been developed and are in clinical trials o cases approved for clinical use in treating certain forms of human cancer. Additionally, the investigational drugs are being developed to target ea E5 ? E5 E7 E7 E7 E7 E7 E7 E6 E6 E6 E6 E6 E6 E7 E6 E6 Hanahan &  Weinberg  Cell  144:  646-­‐74,   2011 Mesri,  Feitelson &  Munger   Cell  Host  &Microbes   15:  266-­‐82, 2014 High-­‐risk  alpha  HPV  carcinogenesis
10. How  can  two  small  proteins  affect  so  many  pathways? E6  and  E7  target: Multifunctional,  non-­‐redundant  cellular  proteins Jordan Miranda Biochemistry  and  biology  of  beta  and  gamma   HPVs Mouse  model  for  papillomavirus  pathogenesis   (Collaboration  with  PF  Lambert,  U  Wisconsin)   Katie Effects  of  HPV  E6/E7  on  host  cell  metabolism
11. Noncoding  RNAs  (miRs etc) How  can  two  small  proteins  affect  so  many  pathways? E6  and  E7  target: Multifunctional,  non-­‐redundant  cellular  proteins Surendra Mallory E6/E7  mediated  dysregulation of  cellular  miRs E6/E7  mediated  dysregulation  of  cellular  lncRNAs
12. Epigenetic  regulation  of  gene  expression Tyshia E7  mediated  dysregulation of  polycomb  repression Discovery  of  epigenetic  factors  that  are  specifically   necessary  for  survival  of  E6/E7  expressing  cells How  can  two  small  proteins  affect  so  many  pathways? Noncoding  RNAs  (miRs etc) E6  and  E7  target: Multifunctional,  non-­‐redundant  cellular  proteins
13. MuPV1  – a  mouse  model  to  study  PV  pathogenesis Patients  with  epidermodysplasia verruciformis  (EV)   high  viral  load,  high  risk  for  skin  cancers. Immunosuppressed  transplant  patients,  heightened   risk  for  skin  cancer. Skin  cancer  in  normal  populations  debated. MmuPV1,  a  mouse  PV  type  capable  of  infecting  lab   strains  of  mice  also  can  cause  formation  of  skin   tumors. Cutaneous  PVs  and  skin  cancer Pictures  courtesy  of  AayushiUberoi (U  Wisconsin)
14. Cellular   Targets RB,  p53 Varying  strengths Alpha   HPVs Beta   HPVs Gamma   HPVs MmuPV MuPV1  – a  mouse  model  to  study  PV  pathogenesis
15. Cellular   Targets Alpha   HPVs Beta   HPVs Gamma   HPVs MmuPV Cellular   Targets Cellular   Targets Cellular   Targets MuPV1  – a  mouse  model  to  study  PV  pathogenesis
16. Beta  and  gamma  E6  and  share  many  cellular  targets    with  MmuPV1  E6 Alpha   HPV E6 Beta   HPV  E6 Gamma   HPV  E6 MmuPV E6 UBE3A + -­‐* + -­‐ TP53   + -­‐ + -­‐ UBE2L3   + -­‐ + -­‐ IRF3   + -­‐ + -­‐ MAML1   -­‐ + + + NOTCH -­‐ + + + MuPV1  – a  mouse  model  to  study  PV  pathogenesis
17. Beta  and  gamma  E6  and  share  many  cellular  targets    with  MmuPV1  E6 Alpha   HPV E6 Beta   HPV  E6 Gamma   HPV  E6 MmuPV E6 UBE3A + -­‐* + -­‐ TP53   + -­‐ + -­‐ UBE2L3   + -­‐ + -­‐ IRF3   + -­‐ + -­‐ MAML1   -­‐ + + + NOTCH -­‐ + + + MuPV1  – a  mouse  model  to  study  PV  pathogenesis
18. Beta  and  gamma  E6  and  share  many  cellular  targets    with  MmuPV1  E6 Alpha   HPV E6 Beta   HPV  E6 Gamma   HPV  E6 MmuPV E6 UBE3A + -­‐* + -­‐ TP53   + -­‐ + -­‐ UBE2L3   + -­‐ + -­‐ IRF3   + -­‐ + -­‐ MAML1   -­‐ + + + NOTCH -­‐ + + + MuPV1  – a  mouse  model  to  study  PV  pathogenesis
19. Beta  and  gamma  E6  and  share  many  cellular  targets    with  MmuPV1  E6 Alpha   HPV E6 Beta   HPV  E6 Gamma   HPV  E6 MmuPV E6 UBE3A + -­‐* + -­‐ TP53   + -­‐ + -­‐ UBE2L3   + -­‐ + -­‐ IRF3   + -­‐ + -­‐ MAML1   -­‐ + + + NOTCH -­‐ + + + MuPV1  – a  mouse  model  to  study  PV  pathogenesis
20. Ongoing  experiments: Is  continued  E6/E7  expression  necessary  for  maintenance   of  cancer  phenotype? What  are  the  co-­‐factors  for  cancer  progression  (UV,   chemical  carcinogens?) What  is  the  significance  of  specific  cellular  targets  for   viral  life  cycle,  pathogenesis,  carcinogenesis? What  are  the  cellular  innate  and  adaptive  immune   response  to  MmuPV1  infection? MuPV1  – a  mouse  model  to  study  PV  pathogenesis