ABSTRACT
The tumour suppressor IRF-1 is a transcription factor involved in the induction of apoptosis in several in vitro systems. Post-lactational involution of the mammary gland is characterized by extensive apoptosis of the epithelial cells. We have previously shown that signal transducer and activator of transcription (Stat) 3 drives apoptosis and involution in the mouse mammary gland. Since one of the downstream targets of the Stat signalling pathway is IRF-1, we have used IRF-1 knockout mice to address the potential role of this transcription factor in involution. Surprisingly, in the absence of IRF-1 significantly higher numbers of apoptotic cells were found in involuting glands at 48 h compared to control glands. In addition, the alveolar structure in IRF-1 null mammary glands had collapsed whereas in control glands the alveoli remained intact and distended. However, by 72 h control and null glands were morphologically similar suggesting that IRF-1 suppresses apoptosis only during the early, reversible, stage of involution. This suggests a survival role for IRF-1 in mammary epithelia and demonstrates a novel role for IRF-1 in vivo--suppression of premature epithelial apoptosis during mammary gland involution.
Subject(s)
Apoptosis , Breast/physiology , DNA-Binding Proteins/physiology , Phosphoproteins/physiology , Animals , Breast/anatomy & histology , Breast/metabolism , Cell Survival , DNA-Binding Proteins/genetics , Female , Gene Expression , Interferon Regulatory Factor-1 , Lactation/metabolism , Mice , Mice, Knockout , Phosphoproteins/genetics , Transcription Factors/genetics , Transcription Factors/physiologyABSTRACT
The recently described family of Smad molecules are essential mediators of transforming growth factor beta (TGF-beta) signalling. To date, seven members of this family have been identified, each of which plays a specific and separate role in mediating TGF-beta superfamily gene transcription. At least two different Smads, Smad2 and Smad4 (DPC4), have been implicated in human cancer and appear to have tumour-suppressor functions. Loss of function of Smad4 is most strongly associated with human pancreatic and colorectal malignancy. Furthermore, work from several different groups has suggested associations between Smad4 loss and malignancy in a number of other tissues. Here, we present a review of the current state of the literature implicating the central Smad mediator, Smad4, in the development of cancer.
