Abstract
Retinoic acid (RA) induces differentiation of S91 melanoma cells through activation of RA receptor (RAR)gamma without affecting cell viability. The novel RARgamma-agonist CD437 (AHPN), however, also induces concomitant apoptosis through an unknown mechanism which was investigated here. By utilizing DNA microarray analysis, five apoptosis-associated, CD437-induced transcripts (CITs) were identified. Interestingly, all CITs are also regulated by p53 in a DNA damage response, and consistent with this interpretation, CD437 was found to cause DNA adduct-formation. However, p53 is not required for CD437-dependent regulation of CITs. Among this set of genes, induction of p21(WAF1/CIP1) is likely to be responsible for early S-phase growth-arrest of CD437-treated cells, whereas ei24 is a critical mediator of CD437-induced apoptosis in S91 cells. These data suggest an RAR-independent mechanism in which CD437 causes DNA adduct-formation, resulting in induction of a p53-independent DNA damage response, and subsequent growth-arrest and apoptosis. CD437-mediated DNA adduct-formation may also explain its apoptotic effects in other cell types.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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Apoptosis / drug effects*
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Apoptosis Regulatory Proteins
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Cell Division / drug effects
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins / genetics
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Cyclins / metabolism
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DNA Adducts / metabolism
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DNA Damage / drug effects
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Gene Expression Regulation, Neoplastic / drug effects
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Melanoma, Experimental / metabolism
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Melanoma, Experimental / pathology*
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Oligonucleotide Array Sequence Analysis
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Oligonucleotides, Antisense / genetics
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Organ Specificity
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism*
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Retinoids / pharmacology*
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S Phase / drug effects
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Transfection
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / physiology
Substances
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Apoptosis Regulatory Proteins
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CD 437
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Cdkn1a protein, mouse
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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DNA Adducts
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EI24 protein, human
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Nuclear Proteins
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Oligonucleotides, Antisense
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Phosphoproteins
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RNA, Messenger
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Receptors, Retinoic Acid
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Retinoids
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Tumor Suppressor Protein p53