Nhận diện các oncogen mới hợp tác với Ras trong Drosophila melanogaster: Đường dẫn RhoGEF/Rho-Family/JNK là động lực chính của quá trình ung thư hóa

Genetics - Tập 188 Số 1 - Trang 105-125 - 2011
Anthony M. Brumby1,1, Karen Goulding2, Tanja Schlosser3, Sherene Loi4, Ryan Galea5,5, Peytee Khoo2, Jessica E. Bolden2, Toshiro Aigaki6, Patrick O. Humbert5, Helena E. Richardson1,5,5
1Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Victoria, Australia
2Cell Cycle and Development lab, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia,
3Cell Cycle and Cancer Genetics lab, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia,
4Breast Cancer Translational Research Laboratory (BCTL), Jules Bordet Institute, Brussels, Belgium,
5Department of Biochemistry and Molecular Biology , University of Melbourne, Melbourne, Victoria, Australia and
6Department of Biological Sciences, Tokyo Metropolitan University, Tokyo, Japan

Tóm tắt

Tóm tắt

Chúng tôi đã chỉ ra trước đây rằng các đột biến trong các yếu tố điều chỉnh tính phân cực tế bào apico-basal hợp tác với Ras oncogenic (RasACT) để thúc đẩy quá trình ung thư ở Drosophila melanogaster và tế bào động vật có vú. Để xác định các gen mới hợp tác với RasACT trong quá trình ung thư hóa, chúng tôi đã thực hiện sàng lọc toàn bộ hệ gen để tìm các gen mà khi được biểu hiện quá mức trong mắt Drosophila đang phát triển sẽ tăng cường sự phì đại do RasACT thúc đẩy. Các gen hợp tác với RasACT được xác định là Rac1, Rho1, RhoGEF2, pbl, rib, và east, những gen này mã hóa cho các yếu tố điều chỉnh hình thái tế bào. Trong một bối cảnh đồng phân (clonal setting), điều này cho thấy các gen mang lại lợi thế cạnh tranh so với tế bào hoang dã, chỉ Rac1, một alen hoạt hóa của Rho1 (Rho1ACT), RhoGEF2, và pbl đã hợp tác với RasACT, dẫn đến giảm sự phân hóa và tạo thành các khối u xâm lấn lớn. Sự biểu hiện của RhoGEF2 hoặc Rac1 cùng với RasACT đã tăng cường hoạt động của Jun kinase (JNK), và việc tăng cường JNK là cần thiết cho sự hợp tác. Tuy nhiên, trong hệ thống toàn bộ mô, việc tăng cường JNK một mình không đủ để hợp tác với RasACT, trong khi trong bối cảnh đồng phân, việc tăng cường JNK là đủ cho quá trình ung thư hóa do RasACT điều khiển. Sự tăng cường JNK cũng đủ để tạo ra sự phát triển xâm lấn của các tế bào biểu mô vú MCF10A biểu hiện RasV12. Nhất quán với điều này, các khối u vú ở người HER2+ (nơi mà yếu tố tăng trưởng biểu bì người 2 được biểu hiện quá mức và tín hiệu Ras được tăng cường) cho thấy một mối tương quan đáng kể với chữ ký biểu thị hoạt hóa đường dẫn JNK. Hơn nữa, phân tích di truyền của chúng tôi ở Drosophila đã chỉ ra rằng Rho1 và Rac đóng vai trò quan trọng trong việc hợp tác của sự biểu hiện quá mức RhoGEF2 hoặc Pbl và các đột biến trong các yếu tố điều chỉnh tính phân cực, Dlg và aPKC, với RasACT trong bối cảnh toàn bộ mô. Tổng thể, phân tích của chúng tôi cho thấy tầm quan trọng của đường dẫn RhoGEF/Rho-family/JNK trong quá trình ung thư hóa hợp tác với RasACT.

Từ khóa


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