Comparative analysis of SV40 17kT and LT function in vivo demonstrates that LTs C-terminus re-programs hepatic gene expression and is necessary for tumorigenesis in the liver

Sarah A Comerford, N. Schultz, E. A. Hinnant, S. Klapproth, Robert E Hammer

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6 Citations (Scopus)

Abstract

Transformation by Simian Virus 40 (SV40) large T antigen (LT) is mediated in large part by its interaction with a variety of cellular proteins at distinct binding domains within LT. While the interaction of LTs N-terminus with the tumor suppressor Rb is absolutely required for LT-dependent transformation, the requirement for the interaction of LTs C-terminus with p53 is less clear and cell-and context-dependent. Here, we report a line of transgenic mice expressing a doxycycline-inducible liver-specific viral transcript that produces abundant 17kT, a naturally occurring SV40 early product that is co-linear with LT for the first 131 amino acids and that binds to Rb, but not p53. Comparative analysis of livers of transgenic mice expressing either 17kT or full length LT demonstrates that 17kT stimulates cell proliferation and induces hepatic hyperplasia but is incapable of inducing hepatic dysplasia or promoting hepatocarcinogenesis. Gene expression profiling demonstrates that 17kT and LT invoke a set of shared molecular signatures consistent with the action of LTs N-terminus on Rb-E2F-mediated control of hepatocyte transcription. However, 17kT also induces a unique set of genes, many of which are known transcriptional targets of p53, while LT actively suppresses them. LT also uniquely deregulates the expression of a subset of genes within the imprinted network and rapidly re-programs hepatocyte gene expression to a more fetal-like state. Finally, we provide evidence that the LT/p53 complex provides a gain-of-function for LT-dependent transformation in the liver, and confirm the absolute requirement for LTs C-terminus for liver tumor development by demonstrating that phosphatase and tensin homolog (PTEN)-deficiency readily cooperates with LT, but not 17kT, for tumorigenesis. These results confirm independent and inter-dependent functions for LTs N-and C-terminus and emphasize differences in the requirements for LTs C-terminus in cell-type dependent transformation.

Original languageEnglish (US)
Article numbere28
JournalOncogenesis
Volume1
Issue number9
DOIs
StatePublished - 2012

Fingerprint

Simian virus 40
Viral Tumor Antigens
Carcinogenesis
Gene Expression
Liver
Transgenic Mice
Hepatocytes
Doxycycline
Gene Expression Profiling
Phosphoric Monoester Hydrolases
Genes
Hyperplasia
Neoplasms
Cell Proliferation

Keywords

  • 17kT
  • HCC
  • LT
  • p53
  • PTEN
  • re-programming

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

@article{31613beb8bbe422087f9576271b6b0f9,
title = "Comparative analysis of SV40 17kT and LT function in vivo demonstrates that LTs C-terminus re-programs hepatic gene expression and is necessary for tumorigenesis in the liver",
abstract = "Transformation by Simian Virus 40 (SV40) large T antigen (LT) is mediated in large part by its interaction with a variety of cellular proteins at distinct binding domains within LT. While the interaction of LTs N-terminus with the tumor suppressor Rb is absolutely required for LT-dependent transformation, the requirement for the interaction of LTs C-terminus with p53 is less clear and cell-and context-dependent. Here, we report a line of transgenic mice expressing a doxycycline-inducible liver-specific viral transcript that produces abundant 17kT, a naturally occurring SV40 early product that is co-linear with LT for the first 131 amino acids and that binds to Rb, but not p53. Comparative analysis of livers of transgenic mice expressing either 17kT or full length LT demonstrates that 17kT stimulates cell proliferation and induces hepatic hyperplasia but is incapable of inducing hepatic dysplasia or promoting hepatocarcinogenesis. Gene expression profiling demonstrates that 17kT and LT invoke a set of shared molecular signatures consistent with the action of LTs N-terminus on Rb-E2F-mediated control of hepatocyte transcription. However, 17kT also induces a unique set of genes, many of which are known transcriptional targets of p53, while LT actively suppresses them. LT also uniquely deregulates the expression of a subset of genes within the imprinted network and rapidly re-programs hepatocyte gene expression to a more fetal-like state. Finally, we provide evidence that the LT/p53 complex provides a gain-of-function for LT-dependent transformation in the liver, and confirm the absolute requirement for LTs C-terminus for liver tumor development by demonstrating that phosphatase and tensin homolog (PTEN)-deficiency readily cooperates with LT, but not 17kT, for tumorigenesis. These results confirm independent and inter-dependent functions for LTs N-and C-terminus and emphasize differences in the requirements for LTs C-terminus in cell-type dependent transformation.",
keywords = "17kT, HCC, LT, p53, PTEN, re-programming",
author = "Comerford, {Sarah A} and N. Schultz and Hinnant, {E. A.} and S. Klapproth and Hammer, {Robert E}",
year = "2012",
doi = "10.1038/oncsis.2012.27",
language = "English (US)",
volume = "1",
journal = "Oncogenesis",
issn = "2157-9024",
publisher = "Nature Publishing Group",
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T1 - Comparative analysis of SV40 17kT and LT function in vivo demonstrates that LTs C-terminus re-programs hepatic gene expression and is necessary for tumorigenesis in the liver

AU - Comerford, Sarah A

AU - Schultz, N.

AU - Hinnant, E. A.

AU - Klapproth, S.

AU - Hammer, Robert E

PY - 2012

Y1 - 2012

N2 - Transformation by Simian Virus 40 (SV40) large T antigen (LT) is mediated in large part by its interaction with a variety of cellular proteins at distinct binding domains within LT. While the interaction of LTs N-terminus with the tumor suppressor Rb is absolutely required for LT-dependent transformation, the requirement for the interaction of LTs C-terminus with p53 is less clear and cell-and context-dependent. Here, we report a line of transgenic mice expressing a doxycycline-inducible liver-specific viral transcript that produces abundant 17kT, a naturally occurring SV40 early product that is co-linear with LT for the first 131 amino acids and that binds to Rb, but not p53. Comparative analysis of livers of transgenic mice expressing either 17kT or full length LT demonstrates that 17kT stimulates cell proliferation and induces hepatic hyperplasia but is incapable of inducing hepatic dysplasia or promoting hepatocarcinogenesis. Gene expression profiling demonstrates that 17kT and LT invoke a set of shared molecular signatures consistent with the action of LTs N-terminus on Rb-E2F-mediated control of hepatocyte transcription. However, 17kT also induces a unique set of genes, many of which are known transcriptional targets of p53, while LT actively suppresses them. LT also uniquely deregulates the expression of a subset of genes within the imprinted network and rapidly re-programs hepatocyte gene expression to a more fetal-like state. Finally, we provide evidence that the LT/p53 complex provides a gain-of-function for LT-dependent transformation in the liver, and confirm the absolute requirement for LTs C-terminus for liver tumor development by demonstrating that phosphatase and tensin homolog (PTEN)-deficiency readily cooperates with LT, but not 17kT, for tumorigenesis. These results confirm independent and inter-dependent functions for LTs N-and C-terminus and emphasize differences in the requirements for LTs C-terminus in cell-type dependent transformation.

AB - Transformation by Simian Virus 40 (SV40) large T antigen (LT) is mediated in large part by its interaction with a variety of cellular proteins at distinct binding domains within LT. While the interaction of LTs N-terminus with the tumor suppressor Rb is absolutely required for LT-dependent transformation, the requirement for the interaction of LTs C-terminus with p53 is less clear and cell-and context-dependent. Here, we report a line of transgenic mice expressing a doxycycline-inducible liver-specific viral transcript that produces abundant 17kT, a naturally occurring SV40 early product that is co-linear with LT for the first 131 amino acids and that binds to Rb, but not p53. Comparative analysis of livers of transgenic mice expressing either 17kT or full length LT demonstrates that 17kT stimulates cell proliferation and induces hepatic hyperplasia but is incapable of inducing hepatic dysplasia or promoting hepatocarcinogenesis. Gene expression profiling demonstrates that 17kT and LT invoke a set of shared molecular signatures consistent with the action of LTs N-terminus on Rb-E2F-mediated control of hepatocyte transcription. However, 17kT also induces a unique set of genes, many of which are known transcriptional targets of p53, while LT actively suppresses them. LT also uniquely deregulates the expression of a subset of genes within the imprinted network and rapidly re-programs hepatocyte gene expression to a more fetal-like state. Finally, we provide evidence that the LT/p53 complex provides a gain-of-function for LT-dependent transformation in the liver, and confirm the absolute requirement for LTs C-terminus for liver tumor development by demonstrating that phosphatase and tensin homolog (PTEN)-deficiency readily cooperates with LT, but not 17kT, for tumorigenesis. These results confirm independent and inter-dependent functions for LTs N-and C-terminus and emphasize differences in the requirements for LTs C-terminus in cell-type dependent transformation.

KW - 17kT

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KW - re-programming

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