STAT5 AS A TARGET FOR REGULATION BY EXTRACELLULAR-MATRIX

Transcription of tissue-specific genes in mammary gland requires signa ls from both prolactin and basement membrane. Here we address the mech anism by which this specialized extracellular matrix regulates transcr iption. Using mammary cell cultures derived from transgenic mice harbo ring the ovine beta-lactoglobulin gene, we show that either a basement membrane extract, or purified laminin-1, induced high levels of beta- lactoglobulin synthesis. It is known that prolactin signals through St at5 (signal transducer and activator of transcription). This transcrip tion factor interacts with gamma-interferon activation site-related mo tifs within the beta-lactoglobulin promoter, which we show are require d for matrix dependence of beta-lactoglobulin expression. The DNA bind ing activity of Stat5 was present only in extracts of mammary cells cu ltured on basement membrane, indicating that the activation state of S tat5 is regulated by the type of substratum the cell encounters. Thus, basement membrane controls transcription of milk protein genes throug h the Stat5-mediated prolactin signaling pathway, providing a molecula r explanation for previous studies implicating extracellular matrix in the control of mammary differentiation.