# RETINOIC ACID IN DIFFERENTIATION AND CARCINOGENESIS

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 1993 · $316,685

## Abstract

Retinoic acid (RA), a natural metabolite of retinol (vitamin A), is a
powerful signalling molecule that influences the differentiation programs
of many types of cells throughout life.  RA also affects morphogenesis
and pattern formation (the formation of structures such as the brain,
face, limbs, etc. during embryogenesis).  Moreover, RA can inhibit or
reverse the process of malignant transformation in some cell types.  How
does RA accomplish this?  Increasing evidence indicates that RA, acting
through nuclear receptors (RARs and RXRs), regulates the expression of
a number of different genes that encode transcription factors.  We
previously demonstrated that in F9 embryonic teratocarcinoma stem cells,
RA treatment results in the rapid activation of the expression of the
homeobox gene Hox 1.6 (formerly named ERA-1) and conversely, in the rapid
decrease in the rate of transcription of the transcription factor REX-1.
We have also identified an RA-sensitive enhancer several kilobases 3' of
the Hox 1.6 gene through which the Hox 1.6 gene is directly activated by
RA in F9 cells.  These results demonstrate a molecular link between RA
action and homeobox gene expression for the first time.  We now want to
determine 1) what regulatory proteins in addition to the RARs interact
with this enhancer DNA, 2) whether this enhancer is the major enhancer
that regulates Hox 1.6 expression in the embryo, and 3) if this enhancer
is a "master" enhancer that regulates the expression of other Hox genes
in the Hox 1 cluster.  Therefore, this RA-sensitive enhancer will be
further characterized and dissected at a molecular level by using gel
retardation assays, DNAse I footprinting, and in vivo footprinting
techniques to identify potential regulatory proteins that bind to the
enhancer DNA in F9 cells.  Whether the enhancer regulates Hox 1.6
expression and the expression of other Hox genes in the Hox 1 cluster in
the embryo will be addressed by the creation of appropriate transgenic
mice that carry Hox 1.6/beta-galactosidase transgenes + the enhancer, and
by knocking out both copies of enhancer DNA by homologous recombination.
We also plan to identify the target genes regulated by the Hox 1.6
homeoprotein; this will be accomplished by employing cell lines that
overexpress the Hox 1.6 gene vs. F9 wild type cells for differential
screening of F9 cDNA libraries.  We have some data suggesting that some
of the Hox 1.6 target genes may be involved in the regulation of cell
shape.  We will use similar experimental approaches, utilizing both the
F9 cell culture model differentiation system and transgenic animals, to
determine how transcription of the REX-1 gene is inhibited by RA and what
REX-1 genomic sequences impart cell type specific expression of REX-1 in
embryos.  The target genes of the REX-1 protein will be identified by
using cell lines in which REX-1 expression is altered for "differential
screening" of libraries or by whole genome PCR.  These studies of the
regulation of...

## Key facts

- **NIH application ID:** 3177685
- **Project number:** 2R01CA039036-10
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **SAM.gov UEI:** YNT8TCJH8FQ8
- **Principal Investigator:** LORRAINE J GUDAS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $316,685
- **Award type:** 2
- **Project period:** 1988-07-01 → 1998-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3177685

## Citation

> US National Institutes of Health, RePORTER application 3177685, RETINOIC ACID IN DIFFERENTIATION AND CARCINOGENESIS (2R01CA039036-10). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3177685. Licensed CC0.

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