Gene Expression Profiling in Cells with Enhanced ?-Secretase Activity

Magold, Alexandra I.; Cacquevel, Matthias; Fraering, Patrick C.

oarray) and cyclin D (4-fold decreased on the microarray) -the latter, as mentioned, is also downregulated by Ptprg. Dvl3 however also interacts with other proteins encoded by candidate genes, among which Nkd1 is of special interest since it links the canonical with the planar cell polarity pathway where it has a different effect on Dvl. The Planar cell polarity pathway through several players, among them Rac (3fold decreased on the microarray) affects gene transcription, as we hypothesize for c-secretase activity changes. Through a chain of different mediators, the planar cell polarity Wnt pathway affects the cytoskeleton. Our microarray has reported some of these mediators to be differentially transcribed as c-secretase activity is enhanced; RhoA transcript levels for example are 3-fold decreased. Rock, which is known to directly interact with the csecretase substrate CD44 (CD44/Rho Family GTPase/ROCK2) [47, 48] , is transcriptionally affected too. Our top candidate UPP1 has only one interaction partner that was also reported to be differentially expressed by the microarray, the cytoskeleton protein vimentin (Vim) [35] . Vimentin itself is not new to AD research, as altered Vim distribution patterns were observed in FAD fibroblasts [36] . Also, UPP1 transcription is regulated by the transcription factor Oct3/4, as is the transcription of another candidate, called SPP1 [49] . Spp1 is a direct interaction partner of the aforementioned c-secretase substrate CD44 and strongly affects Ca 2+ levels [50] . It directly interacts with several proteins encoded by candidate genes, including PKCA, which itself directly interacts with Aplp2, a well-known c-secretase substrate, and Csnk2b, which directly interacts with b-catenin, thus closing the circle.