SPHINGOSINE DEPENDENT KINASE AND CARCINOGENESIS

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A class of protein kinases activated by sphingosine (Sph) or N,N- dimethylsphingosine (DMS), but not by Cer, Sph-1-P, or other sphingolipids or phospholipids, was found by us and termed "sphingosine-dependent protein kinases" (SDKs). One SDK, termed SDK1, specifically phosphorylates certain isoforms 14-3-3 protein ( eta ,beta, zeta) but not others (sigma, tau). Another SDK (SDK2) phosphorylates calreticulin and protein disulfide isomerase. A third SDK (SDK3) phosphorylates heat shock protein and glucose regulated protein. Thus, substrates of all SDKs so far detected are adapters/molecular chaperones controlling homeostasis and signal transduction. We also found that Sph and DMS inhibit bcl-2 gene expression, and activate tyrosine phosphatase MKP-1 to inhibit MAPK, with consequent inhibition of cell growth and induction of apoptosis. Based on these preliminary findings, we propose to study: (1) Characterization and cloning of SDK1, SDK2, SDK3, and their genes, which will facilitate our understanding of the functional role of Sph and DMS in maintaining homeostasis and signal transduction. (2) Mechanisms of the growth-inhibitory and apoptosis-inducing effects of Sph and DMS, with special focus on their (i) activation of MKP-1, and (ii) inhibition of bcl-2 oncogene expression. Our preliminary studies also indicate that oral administration of DMS or its water-soluble derivative N,N,N-trimethyl-Sph (TMS) inhibits intestinal and colorectal cancer development in CF1 mice induced by methylazoxymethanol acetate. We will perform systematic studies on the effect of DMS and TMS added to diet. In the inhibitory effect is confirmed, its mechanism will be studied in relation to activities of SDKs, MAPK, bcl-2, and other signal transducers.