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Sci. STKE, 11 February 2003
Vol. 2003, Issue 169, p. tw59
[DOI: 10.1126/stke.2003.169.tw59]


Cancer Biology More Aggressive Tumors with Ras and Without NF-{kappa}B

Mutations that activate Ras, a protein involved in activating the mitogen-activated protein kinase (MAPK) cascade that regulates cell proliferation, are found in many human cancers. Signaling through the NF-{kappa}B pathway is also involved in controlling proliferation, especially through regulation of apoptosis (see Bolotin and Fuchs). Dajee et al. found a correlation in the characteristics of human squamous cell carcinomas (SCCs) and human skin cells transfected with activated Ras and a stable inhibitor of NF-{kappa}B I{kappa}Bα (referred to as Ras-I{kappa}Bα cells). Similar to SCCs in humans, these transfected cells were neoplastic and invasive when grafted into immune-deficient mice. At the molecular level, both SCCs and Ras-I{kappa}Bα cells exhibited increased levels of the NF-{kappa}B subunit p65 in the cytoplasm and increased phosphorylation of MAPK targets. In these cells, activated Ras can promote G1 arrest through stimulation of cyclin-dependent kinase (CDK) inhibitors and reduction in the levels of CDK4. In the Ras-I{kappa}Bα cells, these responses to activated Ras were blocked, and the cells proceeded through the cell cycle. Similarly, activated Ras inhibited I{kappa}Bα-induced increase in apoptosis in response to tumor necrosis factor. Thus, the Ras-I{kappa}Bα cells were more likely to replicate and less likely to undergo programmed cell death than cells expressing only activated Ras or stabilized I{kappa}Bα. In addition to similarities in signaling, SCCs and Ras-I{kappa}Bα cells also had high levels of expression of laminin 5 and integrin α6β4. Function-blocking antibodies to either protein prevented tumorigenesis of the Ras-I{kappa}Bα cells. Likewise, tumors did not form if Ras and I{kappa}Bα were coexpressed in cells deficient for either laminin 5 or α6β4 integrin, confirming the importance of matrix interactions in tumorigenesis.

D. Bolotin, E. Fuchs, More than skin deep. Nature 421, 594-595 (2003). [Online Journal]

M. Dajee, M. Lazarov, J. Y. Zhang, T. Cai, C. L. Green, A. J. Russell, M. P. Marinkovich, S. Tao, Q. Lin, Y. Kubo, P. A. Khavari, NF-{kappa}B blockade and oncogenic Ras trigger invasive human epidermal neoplasia. Nature 421, 639-643 (2003). [Online Journal]

Citation: More Aggressive Tumors with Ras and Without NF-{kappa}B. Sci. STKE 2003, tw59 (2003).

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