Stereoselectivity of induction of the retinoblastoma gene product (pRb) dephosphorylation by D-erythro-sphingosine supports a role for pRb in growth suppression by sphingosine.

Abstract

Sphingosine has been shown to inhibit cell growth in many cell lines although the mechanism of this effect remains obscure. More recently, D-erythro-sphingosine has been shown to act as an early inducer of dephosphorylation of the retinoblastoma gene product (pRb) in the lymphoblastic leukemia cell line MOLT-4 [Chao, R., Khan, W., & Hannun, Y.A. (1992) J. Biol. Chem., 267, 23459-23462]. In the current study, the role of the natural D-erythro-sphingosine in regulation of cell growth and pRb dephosphorylation was evaluated using chemically synthesized pure isomers of sphingosine. Of the four possible stereoisomers of sphingosine, D-erythro-sphingosine was most active in inducing dephosphorylation of pRb protein with an EC50% of 0.6 microM whereas its enantiomer L-erythro-sphingosine was 8-fold less potent with an EC50% of 5 microM. The dose responses for inhibition of cell growth were nearly identical to the EC50% for pRb dephosphorylation with D-erythro-sphingosine causing 50% inhibition at 0.6 microM whereas L-erythro-sphingosine was 5-6-fold less potent. All of the stereoisomers were taken up by the cells, and the greater potency of D-erythro-sphingosine was not due to differences in cellular uptake. The metabolism of D-erythro-sphingosine was also studied to evaluate the possible role of sphingosine metabolites on regulation of retinoblastoma protein. Evidence is provided against a role for ceramide or sphingosine 1-phosphate as mediators of the effects of sphingosine on pRb dephosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: M Pushkareva, R Chao, A Bielawska, A H Merrill Jr, H M Crane, B Lagu, D Liotta, Y A Hannun
• Journal: Biochemistry (Biochemistry) Vol. 34 Issue 6 Pg. 1885-92 (Feb 14 1995) ISSN: 0006-2960 [Print] United States
• PMID: 7849048 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fumonisins
• Lysophospholipids
• Mycotoxins
• Retinoblastoma Protein
• sphingosine 1-phosphate
• fumonisin B1
• Sphingosine

Topics

• Cell Death (drug effects)
• Cell Division (drug effects)
• Drug Synergism
• Fumonisins
• Kinetics
• Lysophospholipids
• Mycotoxins (pharmacology)
• Phosphorylation
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Retinoblastoma Protein (metabolism)
• Sphingosine (analogs & derivatives, chemistry, metabolism, pharmacology)
• Stereoisomerism
• Tumor Cells, Cultured