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Nuclear sphingosine 1‐phosphate and lung cancer (96.3)
Author(s) -
Ogretmen Besim
Publication year - 2014
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.28.1_supplement.96.3
Subject(s) - telomerase reverse transcriptase , telomerase , sphingolipid , sphingosine , telomere , sphingosine 1 phosphate , ubiquitin ligase , chemistry , cancer research , microbiology and biotechnology , ubiquitin , biology , biochemistry , dna , receptor , gene
Mechanisms that selectively regulate canonical telomere‐replication and non‐canonical oncogenic functions of telomerase reverse transcriptase (hTERT) are largely unknown. Here, we show that sphingosine kinase‐2 (SK‐2)‐generated nuclear sphingosine 1‐phosphate (S1P), a bioactive sphingolipid, interacts with hTERT, involving the C3‐OH of S1P and the D684 residue of hTERT, which then prevents E3 ubiquitin ligase MKRN1‐dependent hTERT degradation. Accordingly, molecular, genetic or pharmacologic targeting of SK‐2, or inhibition of the S1P/hTERT interaction, decreased hTERT stability, and suppressed orthotopic or xenograft‐driven lung tumor growth, without altering telomere length, by activation of a tumor suppressor TCF21. Expression of wild‐type or catalytically inactive‐hTERT mutant that increased or decreased telomere length, respectively, but not the D684A‐hTERT with altered S1P binding, prevented lung tumor suppression by SK‐2/S1P inhibition.