# MOLECULAR BIOLOGY OF SV40 LARGE T ANTIGEN

> **NIH NIH R01** · DARTMOUTH COLLEGE · 1993 · $230,954

## Abstract

The long term objectives of this proposal are to understand the
fundamental mechanisms by which Simian Virus 40 affects cellular gene
expression and alters cellular growth properties.  Studies of mutant SV40
large T antigens demonstrate that 3 regions of T antigen play critical
roles in immortalization and transformation by SV40.  Two are the regions
through which T antigen forms complexes with p105Rb and p53, tumor
suppressor proteins that act by as yet unknown mechanisms to control
normal cell growth.  A large fraction of human cancers contain mutations
affecting Rb, p53, or both.  Sequences near the N-terminus of T antigen
constitute the third important region and may also interact with a
cellular tumor suppressor protein, though none has yet been identified.

The experiments proposed in this project are directed at increasing our
understanding of how SV40 transforms cells and alters normal cellular
growth control.  Since SV40 affects growth control by interacting with
tumor suppressor proteins, mutants of SV40 T antigen defective for these
interactions are potentially powerful tools to investigate how these
proteins control cellular growth.  Four specific areas will be addressed:

(1)  Large T antigen induces DNA replication and mitosis in quiescent
     cells.  Recombinant adenoviruses expressing mutant or wildtype
     large T antigens will be constructed and used to determine which
     regions and functions of T antigen are required for these cellular
     responses.

(2)  Fusion proteins between T antigen and the hormone binding domain of
     steroid hormone receptors will be constructed and cell lines
     expressing these fusion proteins will be prepared.  Addition of
     hormone to these cells should activate T antigen, leading to
     changes in cellular gene expression.  Subtracted cDNA libraries
     will be prepared to identify genes activated or repressed following
     T antigen expression in quiescent cells.  Characterization of these
     genes will focus on those activated or repressed by wildtype T
     antigen but not by mutant T antigens defective for binding to one
     or more tumor suppressor proteins.  In this way, genes should be
     identified whose expression is altered when p53, Rb, and other
     cellular proteins are sequestered.

(3)  The vast majority of adult human cancers are of epithelial cell
     origin.  Most studies of transformation and immortalization by SV40
     have been conducted in rodent cells or in human fibroblasts.  The
     ability of mutant and wildtype T antigens to extend the lifespan
     and alter the growth properties of human mammary epithelial cells
     will be determined.

(4)  Attempts will be made to identify cellular proteins that interact
     with T antigen through sequences near the N-terminus.  Fusion
     proteins containing glutathione S-transferase and portions of
     wildtype or mutant T antigens will be prepared in bacteria and used
     to screen lambda expression l...

## Key facts

- **NIH application ID:** 3178098
- **Project number:** 2R01CA039259-09
- **Recipient organization:** DARTMOUTH COLLEGE
- **SAM.gov UEI:** EB8ASJBCFER9
- **Principal Investigator:** CHARLES N. COLE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $230,954
- **Award type:** 2
- **Project period:** 1985-04-01 → 1997-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3178098

## Citation

> US National Institutes of Health, RePORTER application 3178098, MOLECULAR BIOLOGY OF SV40 LARGE T ANTIGEN (2R01CA039259-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3178098. Licensed CC0.

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