# GROWTH DIFFERENTIATION CONTROL IN PRIMARY KERATINOCYTES

> **NIH NIH R01** · YALE UNIVERSITY · 1992 · $102,161

## Abstract

The ability to escape from the negative influences of a normal cellular
environment may be an important determinant of tumorigenesis.  The proposed
experiments are aimed at exploring this problem as it relates to the mouse
skin system.  In particular, tumorigenicity of ras-transformed
keratinocytes can be suppressed by normal dermal fibroblasts through the
production of a diffusible inhibitor, which is likely to be TGF-Beta 3.
The role that this form of heterotypic cell interaction plays in control of
skin tumor development will be further explored as follows:  1) Primary
mouse keratinocytes will be made TGF-beta-resistant by transformation with
retroviral vectors carrying truncated regions of the E1a oncogene.  By use
of these genes, which are transformation-deficient but still able to induce
TGF-beta resistance, it will be possible to interfere specifically with
negative growth signals of the kind elicited by TGF-Beta, avoiding many
other effects associated with an intact E1a oncogene.  "Mixed
tumorigenicity assays" with dermal fibroblasts and skin reconstitution
experiments will provide two complementary assays to test the genetically
modified keratinocytes under conditions approximating the normal in vivo
situation. 2) Similarly, keratinocytes of transgenic mice will be made
TGF-Beta resistant by use of truncated E1a genes specifically expressed
from a keratin promoter.  The structural and physiological properties of
the skin of the transgenics will be examined as well as their skin tumor
development. 3) The notion that acquisition of TGF-Beta resistance is
required for tumor development will be extended to the possibility of
second changes occurring not in the original, "initiated" cell but in
neighboring ones.  In particular, it will be investigated whether TGF-Beta
3 production and tumor suppressing ability are decreased in genetically
transformed mouse fibroblasts or in fibroblasts derived from certain human
conditions (including particular types of epithelial tumors; genetically
predisposed patients and young versus old individuals).  This work could
provoke some new insights into the basis of tumor predisposition by
environmental and genetic factors and/or aging. 4) The role that TGF-Beta 3
plays in dermal fibroblast tumor suppression will be directly tested by
blocking TGF-Beta 3 expression in cultured dermal fibroblasts by use of
specific antisense RNA retroviral vectors.  The tumor inhibitory effects of
the modified cells will be verified.  5) Finally, a similar approach will
be used to interfere with TGF-Beta 3 expression in dermal fibroblasts of
transgenic mice with negative strand constructs driven by a collagen
promoter.  This should provide important clues as to the role that TGF-Beta
3 plays in normal skin homeostasis as well as development.

## Key facts

- **NIH application ID:** 3159163
- **Project number:** 2R01AR039190-04
- **Recipient organization:** YALE UNIVERSITY
- **SAM.gov UEI:** FL6GV84CKN57
- **Principal Investigator:** GIAN-PAOLO DOTTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1992
- **Award amount:** $102,161
- **Award type:** 2
- **Project period:** 1988-07-01 → 1992-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3159163

## Citation

> US National Institutes of Health, RePORTER application 3159163, GROWTH DIFFERENTIATION CONTROL IN PRIMARY KERATINOCYTES (2R01AR039190-04). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3159163. Licensed CC0.

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