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Regulation of p21 Expression by Sphingosine Kinase 2
Author(s) -
Hait Nitai C,
Milstien Sheldon,
Spiegel Sarah
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.520.6
Subject(s) - sphingosine , sphingosine 1 phosphate , sphingosine kinase 1 , microbiology and biotechnology , sphingosine kinase , chemistry , lipid signaling , sphingolipid , cancer research , biology , biochemistry , receptor
Sphingosine‐1‐phosphate (S1P) is a potent sphingolipid mediator formed by phosphorylation of sphingosine catalyzed by two sphingosine kinase (SphK) isoenzymes, SphK1 and SphK2. Whereas SphK1 is overexpressed in breast cancers and has been linked to cancer progression, not much is known about SphK2. Expression of SphK2, which is enriched in the nucleus of MCF7 human breast cancer cells, increased expression of the cyclin‐dependent kinase inhibitor p21 but had no effect on p53 or its phosphorylation. The phorbol ester PMA is known to induce growth arrest of MCF7 cells accompanied by induction of p21. Indeed, overexpression of SphK2, but not catalytically inactive SphK2, enhanced PMA‐mediated increases in p21 mRNA and protein expression in MCF7 cells. Conversely, downregulation of SphK2 with specific siRNA decreased basal p21 levels as well as its elevation mediated by PMA. Moreover, overexpression of SphK2, but not the inactive mutant, in HeLa cells, where they are also localized to the nucleus, enhanced basal as well as PMA‐stimulated p21‐luciferase promoter activity. Our data support the notion that SphK2 and formation of S1P in the nucleus might be important regulators of p21 transcription. Supported by R01CA61774 to SS.