Activated type I TGFbeta receptor (Alk5) kinase confers enhancedsurvival to mammary epithelial cells and accelerates mammary tumorprogression Page: 5 of 33
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gland (MMTV/PyVmT) inhibits apoptosis and accelerates metastases (Muraoka-Cook et al., 2004). In
MMTV/PyVmT transgenic mice, systemic administration of a soluble TPRII increases tumor cell
apoptosis and reduces metastases (Muraoka et al., 2002a). Also in transformed cells, treatment with
TGFO enhances survival via Akt-induced phosphorylation of FKHRL1 (Shin et al., 2001). TGFO has
been shown to activate PI3K and its target Akt (Bakin et al., 2000; Higaki and Shimokado, 1999; Yi,
2005). Although the signaling programs regulating TGFO-mediated protection from cell death are not
yet clear, in both mesenchymal and epithelial cells, this protection is blocked by the PI3K inhibitor
LY294002 and/or expression of dominant-negative Akt (Horowitz et al., 2004; Muraoka-Cook et al.,
2004; Shin et al., 2001). These data are consistent with the ability of TGFO to behave as a tumor
promoter in late phases of transformation [reviewed in (Wakefield and Roberts, 2002)].
Therefore, to further examine the role of active TGFO signaling in mammary epithelial cell survival
in vivo, we generated transgenic mice expressing a mutant type I receptor (Alk5) containing a
substitution of threonine 204 with aspartic acic (Alk5T204D), which results in constitutive activation of
the receptor serine-threonine kinase in the absence of added ligand (Wieser et al., 1995). Expression of
mutant Alk5TD was directed to mammary epithelium using the mouse mammary tumor virus (MMTV)
promoter. Although ductal extension was delayed during mammary gland mophogenesis, apoptosis was
markedly reduced in pubertal terminal endbuds (TEBs) and during post-lactational involution. Primary
mammary epithelial ells from transgenic glands contained reduced levels of Smad2/3/4 and higher levels
of c-myc compared to wild-type cells, and were insensitive to TGFO-induced anti-mitogenesis. They
also exhibited high levels of ligand-independent PI3K, Akt, and Racl activities, enhanced survival and
adhesion to collagen I and fibronectin, and increased integrin expression. Treatment with an Alk5 kinase
inhibitor upregulated Smad2/3 levels, reduced PI3K activity and P-Akt, and inhibited cell adhesion and
survival, suggesting a causal relation between Alk5TD and the observed phenotypic changes. Finally,
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Muraoka-Cook, Rebecca S.; Shin, Incheol; Yi, Jae Youn; Easterly,Evangeline; Barcellos-Hoff, Mary Helen; Yingling, Jonathan M. et al. Activated type I TGFbeta receptor (Alk5) kinase confers enhancedsurvival to mammary epithelial cells and accelerates mammary tumorprogression, article, January 2, 2005; Berkeley, California. (https://digital.library.unt.edu/ark:/67531/metadc782778/m1/5/: accessed April 25, 2019), University of North Texas Libraries, Digital Library, https://digital.library.unt.edu; crediting UNT Libraries Government Documents Department.