Low dose beta-carotene supplementation of ferrets attenuates smoke-induced lung phosphorylation of JNK, p38 MAPK, and p53 proteins.
We demonstrated previously that smoke exposure and/or high-dose beta-carotene supplementation decreases levels of retinoic acid and retinoic acid receptor beta (RARbeta) protein, but increase levels of c-Jun and proliferating cellular nuclear antigen protein in the lungs of ferrets. In contrast, low-dose beta-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 beta-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 beta-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 beta-carotene. Both phosphorylated-p53 and total p53 were substantially increased in the lungs of these groups. In contrast, low-dose beta-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 beta-carotene supplementation. These data indicate that restoration of retinoic acid and MKP-1 by low-dose beta-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 beta-carotene supplementation are related to the dosage of beta-carotene administered.
Nutrition and Cancer Biology Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Chun
C
Liu
Robert M
RM
Russell
Xiang-Dong
XD
Wang
D000818:Animals; D005289:Ferrets; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000187:drug effects* / Q000201:enzymology; D048670:MAP Kinase Kinase 4; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D012906:Smoke / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D019207:beta Carotene / Q000627:therapeutic use*; D048051:p38 Mitogen-Activated Protein Kinases
D012906:Smoke; D016159:Tumor Suppressor Protein p53; D019207:beta Carotene; D010770:Phosphotransferases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases