CREB3L1 and cancer: Furthermore, because DOX stimulates production of ceramide, which in turn triggers regulated intramembrane proteolysis (RIP) of CREB3L1, allowing the cleaved nuclear form of the protein to activate p21 and other genes that inhibit cell proliferation,12,14 the overall sensitivity of cancer cells to DOX-mediated RIP might depend on generation of different signals in the ER to activate their unique set(s) of target genes.42