Activating transcription factor 4 overexpression inhibits proliferation and differentiation of mammary epithelium resulting in impaired lactation and accelerated involution
Authors: Rakesh Kumar
Rozita Bagheri-Yarmand
Ratna K Vadlamudi
Journal: Journal of Biological Chemistry (2003)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: ATF4; mammary gland development; proliferation; differentiation; p21(WAF1)
Affiliations: Department of Molecular and Cellular Oncology, The University of Texas M D Anderson Cancer Center, Houston, Texas 77030, USA. 

Abstract:  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 p21(WAF1) and p27(Kip1). In addition, there was also impaired lactation accompanied by decreased expression of alpha-lactoalbumin, whey acidic protein, and beta-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. 

Retracted: No

PubPeer comments:
 Figure 1D. Much more similar than expected. https: imgur.com 7Vk30qA , 
 #1 Where it says in this thread **erratum (sic) - see details here**, it does not work. I suspect that this is just one of the ways that the ghastly PubMed redesign actively hampers researchers seeking information to aid their research activities. But it would be good if PubPeer can fix the links to errata. I did get there in the end. It turns out that Fig. 1D is one of four dodgy images replaced in the 2013 correction. Who knows how JBC got notified? Perhaps proto-figure sleuths were beginning to evolve to occupy a niche in the primordial swamps of disinformation way back when? Text of the correction notice: *The original versions of Figs. 1 (D and E), 4A, and 10A in the vinculin, endo-ATF4, K18, and phospho-Stat3 lanes contain errors. Lanes in the vinculin panel of Fig. 1D were duplicated. Images from lanes in the endo-ATF4 panel of Fig. 1E were combined from separate parts of the original image without indicating that the images had been spliced. Lane 2 of the K18 panel of Fig. 4A contained a band that was copied from a separate image. Lanes in the phospho-Stat3 panel of Fig. 10A were duplicated. We have now replaced these panels with results from new experiments using material from the original experiment. These revisions do not change the results or interpretations of this article.* This was, of course, all back in the era when JBC was a bit soft. Not sure whether this damaged article would pass muster in the new dawn since JBC has had a Data Integrity Manager? ,