Research Papers: Autophagy and Cell Death:
Expression of the mRNA stability regulator Tristetraprolin is required for lactation maintenance in the mouse mammary gland
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María Victoria Goddio1, Albana Gattelli1, Johanna M. Tocci1, Lourdes Pérez Cuervo1, Micaela Stedile1, Deborah J. Stumpo3, Nancy E. Hynes2, Perry J. Blackshear3, Roberto P. Meiss4 and Edith C. Kordon1
1IFIBYNE-UBA-CONICET, Departamento de Química Biológica, FCEN-UBA, Buenos Aires, Argentina
2Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
3Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, USA
4National Academy of Medicine, Buenos Aires, Argentina
Edith C. Kordon, email: [email protected]
Keywords: lactation; Tristetraprolin; TNF alpha; cell death; mammary involution; Autophagy
Received: July 10, 2017 Accepted: November 14, 2017 Published: January 03, 2018
Tristetraprolin (TTP), an mRNA-binding protein that negatively controls levels of inflammatory factors, is highly expressed in the lactating mouse mammary gland. To determine the biological relevance of this expression profile, we developed bi-transgenic mice in which this protein is specifically down-regulated in the secretory mammary epithelium in the secretory mammary epithelium during lactation. Our data show that TTP conditional KO mice produced underweight litters, possibly due to massive mammary cell death induced during lactation without the requirement of additional stimuli. This effect was linked to overexpression of inflammatory cytokines, activation of STAT3 and down-regulation of AKT phosphorylation. Importantly, blocking TNFα activity in the lactating conditional TTP KO mice inhibited cell death and similar effects were observed when this treatment was applied to wild-type animals during 48 h after weaning. Therefore, our results demonstrate that during lactation TTP wards off early involution by preventing the increase of local inflammatory factors. In addition, our data reveal the relevance of locally secreted TNFα for triggering programmed cell death after weaning.
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