Sphingosine kinase 1 overexpression stimulates intestinal epithelial cell proliferation through increased c-Myc translation

Abstract

Sphingosine-1-phosphate (S1P), through mechanisms that are not completely understood, is shown to modulate cellular proliferation, which is critically important for maintaining the integrity of intestinal epithelium. Here, we show that increased S1P promotes proliferation in intestinal epithelial cells. We found that overexpression of sphingosine kinase 1 (SphK1), the rate-limiting enzyme for S1P synthesis, significantly increased cell proliferation and that this occurred through enhanced expression of c-Myc. Further, we found that the increased pattern of expression of c-Myc occurred predominantly due to its increased translation. The overexpressed SphK1 led to increased checkpoint kinase 2 and enhanced HuR phosphorylation which allowed for increased translation of c-Myc mRNA through HuR binding at the 3′-untranslated regions. Our findings demonstrate that S1P modulates intestinal cell proliferation and provides new insights as to the mechanistic actions of SphK1 and S1P in maintaining intestinal epithelial homeostasis.

The Sphingosine Kinase 1/Sphingosine-1-Phosphate Pathway in Pulmonary Arterial Hypertension

“…Our results demonstrate that S1P promotes PASMC proliferation in a dose-dependent manner, suggesting that in addition to its effects on pulmonary vascular tone, the SphK1/S1P signaling pathway plays a significant role in the pulmonary vascular remodeling associated with PAH. These novel data are consistent with the observation that S1P promotes proliferation of human satellite cells (24), human intestinal epithelial cells (30), quiescent Swiss 3T3 fibroblast (31), NIH 3T3 fibroblast (4), rat aortic smooth muscle cells (32), and endothelial cells (33). In addition, S1P regulates the expression of proapoptotic and antiapoptotic proteins.…”

Sphingosine Kinase 1 Signaling Promotes Metastasis of Triple-Negative Breast Cancer

“…Previous studies have shown that the SPHK1/S1P signaling can induce activation or inhibition of various transcription factors, including NFkB, E2F, c-Myc, and Sp1, and consequently impact on cell proliferation, apoptosis, and/or inflammation (36,47,48). SPHK1 was reported to induce NFkB activation via intracellular S1P that serves as a cofactor of TRAF2 to activate IKKa/b, then IKKa/b phosphorylates IkBa, resulting in its degradation to allow NFkB activation upon TNFa stimulation (31).…”

Sphingosine kinase 1 (Sphk1) negatively regulates platelet activation and thrombus formation

“…Thus S1pr1-deficient megakaryocytes showed impaired migration of proplatelet extrusions in the circulatory compartment and impaired proplatelet shedding. Beyond that hematopoetic-specific knockout of S1pr1 leads to severe thrombocytopenia (19).In other cell types, S1P participates in the regulation of cell migration, proliferation, and cell adhesion (25, 37), as well as angiogenesis, atherosclerosis, and inflammation (11,23,37,43). Furthermore, S1P is heavily produced and secreted from activated platelets (53).…”

“…In other cell types, S1P participates in the regulation of cell migration, proliferation, and cell adhesion (25,37), as well as angiogenesis, atherosclerosis, and inflammation (11,23,37,43). Furthermore, S1P is heavily produced and secreted from activated platelets (53).…”