Sphingosine kinase regulates hepatoma cell differentiation: roles of hepatocyte nuclear factor and retinoid receptor.
In hepatoma Huh-7 cells, inhibition of sphingosine kinase (SphK) activity by N,N-dimethylsphingosine (DMS) resulted in up-regulated production of liver-specific serum proteins including albumin and alpha-fetoprotein (AFP). The changes in these protein levels coincided well with those of two liver-enriched transcription factors, hepatocyte nuclear factor (HNF)-1 and -4, which regulate a number of liver-specific genes at the transcriptional level. Moreover, DMS induced the expression of retinoic acid receptor-alpha and retinoid X receptor-alpha. In DMS-treated cells, 9-cis retinoic acid (RA) further enhanced HNF-4alpha and albumin expression but it inhibited AFP accumulation. These results suggest that activation of SphK disengages cells from their liver-specific phenotype, and that 9-cis RA further induces differentiation of hepatoma cells when SphK activity is inhibited.
Osawa
Y
Y
First Department of Internal Medicine, Gifu University School of Medicine, Tsukasamachi-40, Gifu 500-8705, Japan.
Nagaki
M
M
Banno
Y
Y
Nozawa
Y
Y
Moriwaki
H
H
Nakashima
S
S
D000077556:Alitretinoin; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D006528:Carcinoma, Hepatocellular; D002454:Cell Differentiation; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D008246:Lysophospholipids; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000502:physiology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012709:Serum Albumin / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014157:Transcription Factors / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000509:alpha-Fetoproteins / Q000378:metabolism; D000099157:Sphingosine Kinase
D000077556:Alitretinoin; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D008246:Lysophospholipids; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012709:Serum Albumin; D013110:Sphingosine; D014157:Transcription Factors; D014212:Tretinoin; D000509:alpha-Fetoproteins; D000099157:Sphingosine Kinase; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; C403128:MLX protein, human; C000607071:RARA protein, human; C060506:sphingosine 1-phosphate; C061800:N,N-dimethylsphingosine