Mad-related genes in the human

Abstract

Resistance to the growth inhibitory effects of TGF-beta is common in human cancers. However, the mechanism(s) by which tumour cells become resistant to TGF-beta are generally unknown. We have identified five novel human genes related to a Drosophila gene called Mad which is thought to transduce signals from TGF-beta family members. One of these genes was found to be somatically mutated in two of eighteen colorectal cancers, and three of the other genes were located at chromosomal positions previously suspected to harbor tumour suppressor genes. These data suggest that this gene family may prove to be important in the suppression of neoplasia, imparting the growth inhibitory effects of TGF-beta-like ligands.

Interleukin‐1β impairment of transforming growth factor β1 signaling by DOWN‐REGULATION of transforming growth factor β receptor type II and up‐regulation of Smad7 in human articular chondrocytes

“…In addition, attenuation of the TGF␤1 response may also be due to a diminished level of intracellular TGF␤1 signaling molecules (R-Smad and/or Co-Smad) or an up-regulation of intracellular inhibitors (I-Smad) (26,27). While the levels of mRNA for Smads 2, 3, and 4 were not affected by IL-1␤, the levels of Smad7 mRNA and protein were increased.…”

Evi1 is a survival factor which conveys resistance to both TGFβ- and taxol-mediated cell death via PI3K/AKT

“…Loss of TGFb responsiveness during colon carcinogenesis has been associated with genetic and epigenetic inactivation of the TGFb type II receptor Parsons et al, 1995), Smad mutations (Riggins et al, 1997), oncogenic activation of K-Ras (Higashidani et al, 2003), and induction of protein kinase C-beta II (Murray et al, 2002). However, the possible role of Evi1 in TGFb signaling in colon cancer is poorly understood.…”

Induction of apoptosis by Smad3 and down-regulation of Smad3 expression in response to TGF-β in human normal lung epithelial cells

“…While seven Smad genes have been reported in the literature thus far, they can be classi®ed into three types according to their functions, i.e., receptor-activated Smads (Smad1 and Smad5 for BMP; Smad2 and Smad3 for TGF-b and activin), co-Smad (Smad4) and anti-Smads (Smad6 and Smad7) Derynck et al, 1996;Eppert et al, 1996;Gra et al, 1996;Hahn et al, 1996;Hayashi et al, 1997;Hoodless et al, 1996;Lechleider et al, 1996;Liu et al, 1996;Riggins et al, 1996;Thomsen, 1996;Topper et al, 1997;Yingling et al, 1996;Zhang et al, 1996). Smad2 and Smad3, the receptor-activated, TGFb signaling Smads, are known to be highly homologous with regard to amino acid sequence and structural characteristics, and both have been found to mediate TGF-b and activin signals by forming heteromers with Smad4 (Eppert et al, 1996;Gra et al, 1996;Riggins et al, 1996;Wrana and Pawson, 1997;Zhang et al, 1996). Despite extensive studies of the Smad gene family, however, no de®nitive di erences in the regulations or functions of these receptor-activated Smads have been identi®ed.…”

“…While Smad4 was ®rst isolated as a pancreatic tumor suppressor gene (Hahn et al, 1996), mutations in the Smad2 and Smad4 genes have also been reported in other common cancers of adults (Eppert et al, 1996;Nagatake et al, 1996;Riggins et al, 1996;Uchida et al, 1996). Our ®ndings that Smad2 and Smad4 both at 18q21 were somatically mutated in a fraction of human lung cancers Uchida et al, 1996) suggested that members of the Smad gene family may play a role in the pathogenesis of lung cancer, since normal lung epithelial cells are known to exhibit a growth-inhibitory response to TGF-b (Masuda et al, 1997;Masui et al, 1986).…”