Role of Rad17 in DNA Damage Checkpoint Signaling and Initiation of Apoptosis in Mammary Cells

摘要

Multi-potent stem cell populations found in adult tissues have been of great interest because they serve as reservoirs for tissue renewal after trauma, disease and aging. One important type of adult stem cell derived from bone marrow is the mesenchymal stem cell (MSC), which contributes to the regeneration of mesenchymal tissues such as bone, cartilage, muscle, tendon and adipose. However, lack of knowledge at the molecular level on the regulatory mechanisms underlying the self-renewal and differentiation of MSCs has limited the potential use of MSCs in practical applications such as tissue engineering and gene therapy. In this report I describe a novel form of crosstalk between the TGF-p and Wnt signaling pathways and its functional role in regulating the proliferation and osteogenic differentiation of human MSCs. We show that TGF-p induces rapid nuclear translocation of p-catenin in MSCs in a Wnt signaling- independent fashion. TGF-p does not affect the stability of p-catenin, but requires the activity of the TGF-p type I receptor and the presence of Smad3. Functionally, this pathway is required for the stimulation of MSC proliferation and the inhibition of MSC osteogenic differentiation by TGF-p likely through the combined actions of p-catenin and Smad3 to regulate downstream target genes. These results provide evidence for a novel mode of cooperation between the TGF-p and Wnt signaling pathways in this specific cellular context, and suggest a potentially important role for this distinct signaling pathway in the control of self-renewal and differentiation of mesenchymal stem cells.