Melnikova Vladislava O, Bolshakov Svetlana V, Walker Christopher, Ananthaswamy Honnavara N
Department of Immunology, The University of Texas MD Anderson Cancer Center, PO Box 301402, Unit 902, Houston, TX 77030, USA.
Oncogene. 2004 Mar 25;23(13):2347-56. doi: 10.1038/sj.onc.1207405.
We have conducted an analysis of genetic alterations in spontaneous murine melanoma cell line B16F0 and its two metastatic clones, B16F1 and B16F10 and the carcinogen-induced murine melanoma cell lines CM519, CM3205, and K1735. We found that unlike human melanomas, the murine melanoma cell lines did not have activating mutations in the Braf oncogene at exon 11 or 15. However, there were distinct patterns of alterations in the ras, Ink4a/Arf, and p53 genes in the two melanoma groups. In the spontaneous B16 melanoma cell lines, expression of p16Ink4a and p19Arf tumor suppressor proteins was lost as a consequence of a large deletion spanning Ink4a/Arf exons 1alpha, 1beta, and 2. In contrast, the carcinogen-induced melanoma cell lines expressed p16Ink4a but had inactivating mutations in either p19Arf (K1735) or p53 (CM519 and CM3205). Inactivation of p19Arf or p53 in carcinogen-induced melanomas was accompanied by constitutive activation of mitogen-activated protein kinases (MAPKs) and/or mutation-associated activation of N-ras. These results indicate that genetic alterations in p16Ink4a/p19Arf, p53 and ras-MAPK pathways can cooperate in the development of murine melanoma.
我们对自发形成的小鼠黑色素瘤细胞系B16F0及其两个转移克隆B16F1和B16F10，以及致癌物诱导的小鼠黑色素瘤细胞系CM519、CM3205和K1735进行了基因改变分析。我们发现，与人类黑色素瘤不同，小鼠黑色素瘤细胞系在Braf癌基因的第11或15外显子没有激活突变。然而，在这两个黑色素瘤组中，ras、Ink4a/Arf和p53基因存在不同的改变模式。在自发的B16黑色素瘤细胞系中，由于跨越Ink4a/Arf外显子1α、1β和2的大片段缺失，p16Ink4a和p19Arf肿瘤抑制蛋白的表达丧失。相比之下，致癌物诱导的黑色素瘤细胞系表达p16Ink4a，但在p19Arf（K1735）或p53（CM519和CM3205）中存在失活突变。致癌物诱导的黑色素瘤中p19Arf或p53的失活伴随着丝裂原活化蛋白激酶（MAPKs）的组成性激活和/或N-ras的突变相关激活。这些结果表明，p16Ink4a/p19Arf、p53和ras-MAPK途径中的基因改变可能协同促进小鼠黑色素瘤的发生发展。
