Mechanisms of action of okadaic acid class tumor promoters on mouse skin

Journal Article · Sat Jun 01 04:00:00 EDT 1991 · Environmental Health Perspectives; (United States)

DOI:https://doi.org/10.1289/ehp.9193211· OSTI ID:5929792

Fujiki, Hirota; Suganuma, Masami; Yoshizawa, Seiji; Nishiwaki, Shinji; Winyar, Boonsong ^[1]; Sugimura, Takashi ^[2]

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1. National Cancer Center Research Inst., Tokyo (Japan)
2. National Cancer Center, Tokyo (Japan)

Okadaic acid, dinophysistoxin-1 (35-methylokadaic acid), and calyculin A are the okadaic acid class of non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which do not bind to the phorbol ester receptors in cell membranes or activate protein kinase C in vitro. They have potent tumor-promoting activities on mouse skin, as strong as TPA-type tumor promoters, such as TPA, teleocidin, and aplysiatoxin. DNA samples isolated from tumors induced by dimethylbenz(a)anthracene and each of the okadaic acid class tumor promoters had the same mutation at the second nucleotide of codon 61 (CAA to CTA) in the c-H-ras gene. Okadaic acid receptors, protein phosphatases 1 and 2A, are present in the particulate as well as cytosolic fractions of various mouse tissues. The apparent activation of protein kinases by the okadaic acid class tumor promoters, after their incubation with {sup 32}P-ATP, protein kinases, and protein phosphatases, was observed. This activation was caused by inhibition of protein phosphatases 1 and 2A by the okadaic acid class tumor promoters. Treatment of primary human fibroblasts and human keratinocytes with the okadaic acid class tumor promoters induced the hyperphosphorylation of a 60-k-Da protein in nuclear and cytosolic fractions, due to the inhibition of protein phosphatases. The 60-kDa protein is a proteolytic fragment of nucleolin, a major nonhistone protein and is designated as N-60. The mechanisms of action of the okadaic acid class tumor promoters are discussed with emphasis on the inhibition of protein phosphatase activity.

• OSTI ID: 5929792
• Journal Information: Environmental Health Perspectives; (United States), Journal Name: Environmental Health Perspectives; (United States) Vol. 93; ISSN 0091-6765; ISSN EVHPA
• Country of Publication: United States
• Language: English

Related Subjects

560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ANIMAL CELLS
ANIMALS
AROMATICS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOLOGICAL EFFECTS
BODY
CARCINOGENS
CONDENSED AROMATICS
CONNECTIVE TISSUE CELLS
DAYS LIVING RADIOISOTOPES
DIMETHYLBENZANTHRACENE
ENZYMES
ESTERASES
ESTERS
FIBROBLASTS
HYDROGEN COMPOUNDS
HYDROLASES
ISOTOPES
KERATIN
LIGHT NUCLEI
MAMMALS
MEMBRANE PROTEINS
MICE
NUCLEI
ODD-ODD NUCLEI
ORGANIC COMPOUNDS
ORGANS
PHORBOL ESTERS
PHOSPHATASES
PHOSPHORUS 32
PHOSPHORUS ISOTOPES
PROMOTERS
PROTEINS
RADIOISOTOPES
RECEPTORS
RODENTS
SCLEROPROTEINS
SKIN
SOMATIC CELLS
TRITIUM COMPOUNDS
TUMOR PROMOTERS
VERTEBRATES