| First Author | Ramakrishna G | Year | 2002 |
| Journal | Toxicol Appl Pharmacol | Volume | 179 |
| Issue | 1 | Pages | 21-34 |
| PubMed ID | 11884234 | Mgi Jnum | J:75236 |
| Mgi Id | MGI:2176119 | Doi | 10.1006/taap.2001.9344 |
| Citation | Ramakrishna G, et al. (2002) Decrease in K-ras p21 and Increase in Raf1 and Activated Erk 1 and 2 in Murine Lung Tumors Initiated by N-Nitrosodimethylamine and Promoted by 2,3,7,8-Tetrachlorodibenzo-p-dioxin. Toxicol Appl Pharmacol 179(1):21-34 |
| abstractText | Recent evidence suggests that K-ras protooncogene protein p21 may have a tumor-suppressive role in the context of development of lung adenocarcinoma. Levels of K-ras p21, raf-1, mitogen-activated protein kinases Erk 1 and 2, the phosphorylated-activated forms of Erk 1 and 2 (Erk 1P and 2P), and proliferating cell nuclear antigen (PCNA) were measured by immunoblotting in mouse lung tumors (5 to 9 mm in size) caused by N-nitrosodimethylamine (NDMA) and in control lungs. In tumors compared with normal lung, cell membrane-associated K-ras p21 was significantly decreased and cytosolic K-ras p21 increased. Total, membrane, and cytosolic raf-1 and Erk 1P and 2P were increased in tumors compared with normal lung. A single dose of 5 nmol/kg 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) given after NDMA resulted in a significant 2.4-fold increase in tumor multiplicity. A significantly greater decrease in membrane-associated K-ras p21 and increase in total and membrane associated raf-1 occurred in the NDMA/TCDD tumors compared with the NDMA-only tumors. PCNA levels increased in tumors, a finding confirmed by immunohistochemistry, and correlated with tumor size after NDMA/TCDD treatment but not after NDMA only. The increase in raf-1 in the tumors was confirmed by immunohistochemistry, which also revealed an increase in raf-1-positive alveolar macrophages specifically associating with tumors from the earliest stages. These results suggest a possible tumor-suppressive function for K-ras p21 in lung and a positive role for raf-1 and Erk 1/2 in lung tumorigenesis. TCDD may promote tumors by contributing to downregulation of K-ras and stimulation of raf-1. (C)2002 Elsevier Science (USA). |
