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Nutrition and Cancer

Low Dose ß-Carotene Supplementation of Ferrets Attenuates Smoke-Induced Lung Phosphorylation of JNK, p38 MAPK, and p53 Proteins¹

Nutrition and Cancer Biology Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111

²To whom correspondence should be addressed. E-mail: chun.liu{at}tufts.edu.

We demonstrated previously that smoke exposure and/or high-dose ß-carotene supplementation decreases levels of retinoic acid and retinoic acid receptor ß (RARß) protein, but increase levels of c-Jun and proliferating cellular nuclear antigen protein in the lungs of ferrets. In contrast, low-dose ß-carotene can prevent the decreased lung retinoic acid and the smoke-induced lung lesions. In the present study, we investigated whether smoke exposure and/or ß-carotene supplementation could affect Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and p53 in the lungs of ferrets. Ferrets were subjected to cigarette smoke exposure and either a high or low dose of ß-carotene (2 x 3 factorial design) for 6 mo. There were greater protein levels of phosphorylated JNK, p38, and c-Jun, but lower levels of MAPK phophatase-1 (MKP-1) in groups exposed to smoke and/or high dose ß-carotene. Both phosphorylated-p53 and total p53 were substantially increased in the lungs of these groups. In contrast, low-dose ß-carotene greatly attenuated the smoke-induced phosphorylation of JNK, p38, c-Jun, p53, and total p53, accompanied by upregulated MKP-1. Smoke exposure increased MAPK kinase-4 (MKK4) phosphorylation regardless of ß-carotene supplementation. These data indicate that restoration of retinoic acid and MKP-1 by low-dose ß-carotene in the lungs of ferrets may prevent the smoke-induced activation of the JNK-dependent signaling pathway, p38 MAPK, and the associated phosphorylation of p53, thereby lowering the risk of the smoke-related lung lesions. These data provide supportive evidence that the beneficial vs. detrimental effects of ß-carotene supplementation are related to the dosage of ß-carotene administered.

KEY WORDS: • ß-carotene • smoke • signal transduction pathway

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