title: 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.
authors.affiliation: Baltimore Veterans Affairs Medical Center, Baltimore, MD 21201, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.forename: Alexis D
authors.initials: AD
authors.lastname: Smith
authors.forename: Ruiyun
authors.initials: R
authors.lastname: Li
authors.forename: Jaladanki N
authors.initials: JN
authors.lastname: Rao
authors.forename: Lan
authors.initials: L
authors.lastname: Liu
authors.forename: James M
authors.initials: JM
authors.lastname: Donahue
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Wang
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Turner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D015854:Up-Regulation / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; C466999:SPHKAP protein, human
keywords: Hur; IEC-6 cells; S1P; SphK1; c-Myc; cell proliferation; polysome analysis; stable transfection