INVESTIGADORES
HALPERIN Julia
congresos y reuniones científicas
Título:
Foxo3a regulation of GALT expression provides a possible mechanism for the ovarian defect in mice expressing only the short form of the PRL receptor
Autor/es:
HALPERIN J, BOWEN-SHAUVER J, MORAN T, LESLIE N, BINART N, KELLY P AND GIBORI G
Lugar:
Evanston, USA
Reunión:
Simposio; 26th Annual Minisymposium on Reproductive Biology; 2005
Institución organizadora:
Northwestern University
Resumen:
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Alternative splicing of the prolactin receptor (PRLR)
generates two isoforms, the short (RS) and long (RL) form. The mechanism by which PRL signals through
the RL has been extensively investigated.
However, little is known about PRL signaling through the RS. To ascertain the role of the RS in the ovary,
PRLR null mice expressing a transgenic RS construct were generated. A severe ovarian defect and premature ovarian
failure were found in these mice. The
ovarian phenotype in the RS transgenic mice is identical to phenotypes found in
both Foxo3a null mice and in women carrying mutations of galactose-1-phosphate
uridyl transferase (GALT). Foxo proteins
are forkhead transcription factors known to regulate genes involved in glucose
metabolism while GALT is an enzyme that converts galactose-1-P to glucose. Deficiencies in GALT lead to galactosemia and
premature ovarian failure. To
investigate whether Foxo3a expression is regulated by PRL signaling through the
RS, ovaries from PRLR null and RS transgenic mice were subjected to microarray
analysis, RT-PCR, or Real Time PCR. We
found that expression of RS in the ovary leads to significant down-regulation
of Foxo3a expression. HepG2 cells were
co-transfected with the full-length 3.3kb GALT promoter along with either a
constitutively active (CA) Foxo3a construct or an empty vector in order to
determine whether Foxo3a regulates GALT expression. Transfection studies showed
a marked up-regulation of the GALT promoter by Foxo3a. A 5 deletion analysis of the GALT promoter
was performed to distinguish the Foxo3a regulatory sites from the six putative
Foxo3a binding sites. Co-transfection
with the truncated promoter-reporter constructs and CA- Foxo3a revealed a
response element, which significantly up-regulated GALT gene expression, at
1011 bp upstream of the ATG site. In
summary, the results indicate that PRL, acting through the short form of the
receptor, down-regulates the expression of Foxo3a affecting the transcription
of GALT. Foxo3a-GALT interaction
provides a possible mechanism for the severe follicular impairment in females
expressing RS. Supported by NIH HD11119
and U54 HD 40093.