Editors' ChoiceApoptosis

Raf Knockouts Reveal an Antiapoptotic Role

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Science's STKE  17 Apr 2001:
Vol. 2001, Issue 78, pp. tw2
DOI: 10.1126/stke.2001.78.tw2

The serine-threonine kinase Raf-1 is thought to be important for promoting cell proliferation; however, the lack of Raf-1 null mice has kept such hypotheses from being conclusive. Two reports describe the effect of Raf-1 mutations in mice. Mikula et al. found that raf-1-/- mice died as embryos and that their fetal livers were hypocellular and had many apoptotic cells. In culture, the number of viable raf-1-/- fibroblasts was slightly reduced, not because of reduced proliferation but because of increased apoptosis. Extracellular-regulated kinase (ERK) activity was normal in raf-1-/- cells, indicating that Raf-1 was not required for stimulating ERK. Hüser et al. created homzygous knockin mice harboring Y340F/Y341F (raf-1FF/FF) mutations. This Raf-1 mutant protein had no detectable kinase activity toward MEK in vitro. raf-1FF/FF mice appeared normal and were capable of producing viable offspring. raf-1FF/FF cells did not exhibit increased apoptosis, suggesting that MEK activity is not important for Raf-1-mediated antiapoptotic effects or for normal development.

M. Mikula, M. Schreiber, Z. Husak, L. Kucerova, J. Rüth, R. Wieser, K. Zatloukal, H. Beug, E. F. Wagner, M. Baccarini, Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J. 20, 1952-1962 (2001). [Abstract] [Full Text]

M. Hüser, J. Luckett, A. Chiloeches, K. Mercer, M. Iwobi, S. Giblett, X.-M. Sun, J. Brown, R. Marais, C. Pritchard, MEK kinase activity is not necessary for Raf-1 function. EMBO J. 20, 1940-1951 (2001). [Abstract] [Full Text]