IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Reduction of tristetraprolin expression triggers early involution in conditional KO mice. Poster
Autor/es:
M. VICTORIA GODDIO; L. PEREZ-CUERVO; J. TOCCI; M. VEGGETTI; R. MEISS; EDITH C.KORDON
Lugar:
Il Ciocco, Barga
Reunión:
Encuentro; Gordon Research Conferences - Mammary Gland Biology; 2014
Resumen:
Mammary gland development is a complex, multistep process. From pregnancy to lactation, lobulo-alveolar growth is followed by the complete differentiation of mammary epithelium, which allows the production and secretion of milk proteins. At weaning, a rapid switch from survival to death signaling occurs, leading to involution, which involves extensive remodeling and an innate immune response in the tissue. Control of mRNA half-life plays a central role in normal development and disease: Several pathological conditions, such as inflammation and cancer, tightly correlate with deregulation in mRNA stability of pro-inflammatory genes. The mRNA half-life of these genes appears to be regulated by mRNA-binding proteins that interact with AU-rich elements (AREs) in the 3´-untranslated region of mRNAs. One of these RNA-binding proteins is tristetraprolin (TTP), which induces degradation of mRNA coding for pro-inflammatory cytokines and invasiveness-associated genes. Our previous results showed that TTP is down-regulated in human breast cancers and abundantly expressed during lactation in the mouse mammary gland. Therefore, we proposed that TTP might play a relevant role maintaining lactation, preventing expression of factors that might trigger early involution of the gland. To test that hypothesis, WAP-Cre recombinase transgenic mice, in which the enzyme is expressed uniquely in the lactating mammary tissue, were crossed with lox-P TTP transgenic animals. Then, we analyzed the mammary tissue at different times after parturition. We found that bi-transgenic females have smaller glands with lower content of milk and, between day 10 and 15 of lactation, mammary gland of these mice displayed clear signs of involution. In addition to morphological alteration of the alveoli, immuno-histochemical, qRT-PCR and western blot analysis showed that these glands display an increase of apoptotic cells in the alveoli, high expression of inflammatory cytokines, e.g. TNF-alpha and LIF, as well as Stat3 activation, among other traits of the involuting gland. These observations indicate that TTP significantly contributes to lactation maintenance in the normal gland, suggesting that its activity as tumor suppressor in the breast might be associated to its capacity to prevent involution-associated events in the mammary gland.