Genetic ablation of S6-kinase does not prevent processing of SREBP1.

The SREBP family of transcription factors regulates the expression of genes involved in fatty acid and cholesterol biosynthesis. The activation of SREBP transcription factors requires proteolytic cleavage of the inactive precursor and nuclear translocation of the mature form of the protein. It has been shown that nuclear accumulation of the mature form of SREBP1 is induced in response to activation of the serine/threonine kinase Akt, an important effector of the Ras/PI3-kinase signalling pathway. Activation of SREBP by Akt depends on the mammalian target of rapamycin complex 1 (mTORC1) but the exact mechanism of this activation remains unclear. We have investigated whether ablation of different signalling molecules downstream of mTORC1 affects expression of SREBP targets genes. We could show that inhibition of S6-kinases 1 and 2 expression using RNA interference did not block induction of expression of fatty acid synthase (FASN) or ATP-citrate lyase (ACLY) following activation of Akt in human retinal pigment epithelial cells. Furthermore, accumulation of mature SREBP1 was not inhibited after combined silencing of S6-kinases 1 and 2. Genetic ablation of both kinases also did not prevent the formation of mature SREBP1 in mouse embryonic fibroblasts. Taken together, these results suggest that S6-kinases 1 and 2 are dispensable for the induction of SREBP processing in the experimental systems used here.