Tristetraprolin (TTP) down-regulation in mammary epithelial cells induces developmental delay and DUSP-6 phosphatase overexpression

Inés Beckerman¹, Micaela Stedile¹, María Victoria Medina¹, Omar Coso¹, Edith Kordon¹


Tristetraprolin (TTP) binds the 3’UTR of its target mRNAs, promoting their degradation. We have determined that reducing TTP expression levels in mammary cells increases expression of pro-inflammatory cytokines and apoptosis. Here, we show that TTP deletion in the mammary epithelium of MMTV-Cre/TTPfl/fl mice caused a delay in ductal elongation and the persistence of terminal end buds in the bi-transgenic adult females. Since we had observed that HC11 TTP knockdown cells (TTP-KD), displayed lower phosphorylated ERK1/2 (pERK) levels than HC11-shControl cells (Ctrl) while growing in complete medium, we proposed that sub-activation of this MAPK might be involved in the observed phenotype. Our results show that although the temporal sequence of ERK phosphorylation upon addition of EGF was not altered in TTP-KD respect to Ctrl, the first showed increased expression of DUSP6, an ERK1/2-specific phosphatase encoded by a TTP-target mRNA. Then, DUSP-6 overexpression may decrease P-ERK levels in proliferative conditions, without altering fast phosphorylation of this MAPK in response to growth factors. In summary, our results confirm the relevance of TTP in the mammary epithelium, suggesting that the activity of this protein on DUSP6 mRNA would be of vital importance for maintaining p-ERK1/2 high levels in proliferative conditions. More studies are underway to verify ERK1/2 and DUSP6 involvement in the MMTV-Cre/TTPfl/fl mouse phenotype.