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J. Biol. Chem., Vol. 278, Issue 19, 17421-17429, May 9, 2003
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From the Department of Molecular and Cellular Oncology, The
University of Texas M. D. Anderson Cancer Center,
Houston, Texas 77030
The basic leucine zipper
containing activating transcription factors (ATFs) modulates the
expression of growth-regulating genes. In this study, we sought to
determine specifically the consequences of ATF4 expression on mammary
gland development in transgenic mice. Overexpression of ATF4 severely
impaired normal development of the mammary gland, which was associated
with reduced proliferation and differentiation of mammary alveolar
epithelium and up-regulation of p21WAF1 and
p27Kip1. In addition, there was also impaired lactation
accompanied by decreased expression of
Activating Transcription Factor 4 Overexpression Inhibits
Proliferation and Differentiation of Mammary Epithelium Resulting
in Impaired Lactation and Accelerated Involution*
,
-lactoalbumin, whey acidic
protein, and 
-casein, possibly because of the down-regulation of
STAT5a tyrosine phosphorylation. Mammary gland involution in
ATF4-transgenic mice was accelerated, compared with wild type
littermates by whole mount analysis. In addition, day 18 of lactation
in transgenic mice was phenotypically equivalent to day 3 of involution
in wild type mice, as determined by the TUNEL assay and expression of Bax. The concentration of the proapoptotic molecule caspase-3 was
increased during lactation in ATF4-transgenic animal. Mammary glands
from ATF4-transgenic mice also showed significant nuclear translocation
of activated STAT3 and up-regulation of one of its target genes,
insulin-like growth factor-binding protein-5, which is thought to
facilitate apoptosis by sequestering insulin-like growth factor.
Together, these findings suggest that ATF4 may play a role during
mammary gland development and that down-regulation of ATF4 may be
important for the onset of involution in the mammary gland.
*
This work was supported by National Institutes of Health
Grant CA 90970, Cancer Center Core Grant CA16672, and the Breast Cancer
Research Program of the University of Texas M. D. Anderson Cancer
Center (to R. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence may be addressed: Dept. of Molecular and
Cellular Oncology, M. D. Anderson Cancer Center, 1515 Holcolmbe Blvd.,
108, Houston, TX 77030. Tel.: 713-745-3558; Fax: 713-745-3792; E-mail: rkumar@mdanderson.org (to R. K.) or
ryarmand{at}manderson.org (to R. B.-Y.).
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