Mcpyv Presentation

The role of Merkel cell polyomavirus in human cancer Qualifying Examination Dominik Satory Department of Molecular and Human Genetics Baylor College of Medicine, Houston, TX Tuesday, September 9, 1:30 P.M. – 3:30 P.M. Room T934

Polyomaviruses ,[object Object],[object Object],[object Object],[object Object],[object Object]

Polyomavirus genome ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],Poulin and DeCaprio, 2006

Polyomavirus life cycle ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],permissive cell nonpermissive cell viral infection cell death transformed cell

Large T-antigen ,[object Object],[object Object],[object Object],Hsc70-binding motif 0 100 200 300 400 500 600 700 817 DnaJ Rb Ori binding Helicase Rb-binding motif C N p53-binding sites

Human polyomaviruses ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],(Feng et al., 2008)

Merkel cell carcinoma (MCC) ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Merkel cell polyomavirus (MCPyV) ,[object Object],[object Object],[object Object],[object Object],C 0 100 200 300 400 500 600 700 817 DnaJ Rb Ori binding Helicase MCV350 MCV339 N

Hypothesis ,[object Object],[object Object],[object Object]

Aims of the project Aim 2: Lytic cycle Aim 1: Transformation and tumorigenesis Aim 3: Expression and interactions of viral proteins

Aim 1 : The transforming and oncogenic potentials of MCPyV tumor transformation genomic integration tumor growth, accumulation of mutations

Aim 1 : The transforming and oncogenic potentials of MCPyV ,[object Object],[object Object]

Transforming potential of MCPyV T-antigen ,[object Object],[object Object],[object Object],[object Object]

Transforming potential of MCPyV T-antigen ,[object Object],[object Object]

Aim 1 : The transforming and oncogenic potentials of MCPyV Does MCPyV T-antigen immortalize human cells? YES NO ,[object Object],[object Object]

MCPyV T-antigen-induced oncogenesis ,[object Object],[object Object],[object Object]

MCPyV T-antigen-induced oncogenesis inject newborn hamsters with the virus examine tumors in hamster’s body polyomavirus induces tumorigenesis presence of virus suggests its oncogenic potential detect viral proteins by IHC and viral DNA by PCR

Aim 1 : The transforming and oncogenic potentials of MCPyV Does MCPyV cause tumors in laboratory animals? YES NO ,[object Object],[object Object],[object Object]

Aim 2 : Identification of WT MCPyV and its potential infectivity infection of permissive cell cell lysis, release of virions virus replication

Aim 2 : Identification of WT MCPyV and its potential infectivity ,[object Object],[object Object]

Identification of WT MCPyV ,[object Object],[object Object],[object Object]

Identification of WT MCPyV ,[object Object],[object Object],[object Object],[object Object],[object Object],MCPyV

Aim 2 : Identification WT MCPyV and test its infectivity Does WT MCPyV exist in humans and the environment? YES NO ,[object Object],[object Object]

Lytic potential of MCPyV ,[object Object],[object Object],[object Object]

Lytic potential of MCPyV ,[object Object]

Aim 2 : Identification WT MCPyV and test its infectivity Is WT MCPyV capable of lytic growth? YES NO ,[object Object],[object Object]

Aim 3 : Mechanism of MCPyV-induced transformation viral gene expression synthesis of viral proteins interactions with cellular proteins

[object Object],[object Object],[object Object],Aim 3 : Mechanism of MCPyV-induced transformation

Expression and interactions of MCPyV proteins ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object],✗

Stability of mRNA and expression of MCPyV proteins ,[object Object],[object Object],TAg (94 kDa) VP1 (44 kDa) actin tumor SV40 MCC antibody SV40 SV40 MCPyV MCPyV TAg TAg TAg TAg VP1 VP1 VP1 VP1

Aim 3 : Mechanism of MCPyV-induced transformation Are MCPyV proteins present in MCC tumors? YES NO ,[object Object],[object Object],[object Object],[object Object]

Interactions of MCPyV proteins ,[object Object],[object Object],[object Object],[object Object],[object Object],[object Object]

Aim 3 : Mechanism of MCPyV-induced transformation Do MCPyV proteins interact with cellular partners? YES NO ,[object Object],[object Object],[object Object],[object Object]

Mutation analysis of TAg TAg transformation 0 100 200 300 400 500 600 700 817 DnaJ Rb Ori binding Helicase MCV350 MCV339 N DnaJ Rb Ori binding N C C Ori binding Helicase C N Helicase C DnaJ Rb N N C

Aim 3 : Mechanism of MCPyV-induced transformation Are p53-binding sites necessary for transformation? YES NO ,[object Object],[object Object],[object Object]

Epistasis analysis of TAg ,[object Object],[object Object]

Aim 3 : Mechanism of MCPyV-induced transformation Is transformation in presence of TAg epistatic with loss of pRb/p53? YES NO ,[object Object],[object Object],[object Object]

Aim 3 : Mechanism of MCPyV-induced transformation Is stability of MCV339 and MCV350 mRNA affected by mutations? YES NO ,[object Object],[object Object]

Summary and Significance ,[object Object],[object Object],[object Object]

Future directions ,[object Object],[object Object],[object Object],[object Object],[object Object]

Mcpyv Presentation

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