Forced involution of the functionally differentiated mammary gland by overexpression of the pro-apoptotic protein bax.
The mammary gland is a developmentally dynamic, hormone-responsive organ that undergoes proliferation and differentiation within the secretory epithelial compartment during pregnancy. The epithelia are maintained by pro-survival signals (e.g., Stat5, Akt1) during lactation, but undergo apoptosis during involution through inactivation of cell survival pathways and upregulation of pro-apoptotic proteins. To assess if the survival signals in the functionally differentiated mammary epithelial cells can override a pro-apoptotic signal, we generated transgenic mice that express Bax under the whey acidic protein (WAP) promoter. WAP-Bax females exhibited a lactation defect and were unable to nourish their offspring. Mammary glands demonstrated: (1) a reduction in epithelial content, (2) hallmark signs of mitochondria-mediated cell death, (3) an increase in apoptotic cells by TUNEL assay, and (4) precocious Stat3 activation. This suggests that upregulation of a single pro-apoptotic factor of the Bcl-2 family is sufficient to initiate apoptosis of functionally differentiated mammary epithelial cells in vivo.
Biology Department, University of Kentucky, Lexington, Kentucky, USA. Edmund.rucker@uky.edu
Edmund B
EB
Rucker
Amber N
AN
Hale
David C
DC
Durtschi
Kazuhito
K
Sakamoto
Kay-Uwe
KU
Wagner
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D005822:Genetic Vectors; D007150:Immunohistochemistry; D007774:Lactation / Q000235:genetics; D008321:Mammary Glands, Animal / Q000196:embryology* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008894:Milk Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D051028:bcl-2-Associated X Protein; C024471:whey acidic proteins; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
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