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Gene Review

Zhx2  -  zinc fingers and homeoboxes 2

Mus musculus

Synonyms: AFP regulator 1, Afr-1, Afr1, Alpha-fetoprotein regulator 1, Raf, ...
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Disease relevance of Zhx2


High impact information on Zhx2

  • Induction of Ras and Raf can be caused by active N-Ras and B-Raf mutants as well as by gene amplification [5].
  • Raf activation is stimulated following its translocation to the plasma membrane, a process that ordinarily requires interaction with the membrane-localized GTPase, Ras-GTP [6].
  • To investigate the mechanisms underlying Raf activation, we have developed a coumermycin-induced chemical dimerization method [6].
  • In revertant cells, DNA replication induced by serum or TPA was eliminated or reduced proportionately to the reduction in Raf protein levels [7].
  • Through this approach the gene encoding heparin-binding epidermal growth factor (HB-EGF) was identified as an immediate-early transcriptional target of oncogenic Raf kinases [8].

Biological context of Zhx2


Anatomical context of Zhx2

  • Thus, Raf-independent signaling events are essential for oncogenic Ras transformation of epithelial cells, but not fibroblasts [12].
  • In summary, our observations demonstrate that oncogenic Ras activation of the Raf/MAP kinase pathway alone is not sufficient for full tumorigenic transformation of RIE-1 epithelial cells [12].
  • A dominant negative mutant of PKC epsilon inhibited both proliferation of NIH 3T3 cells and activation of Raf in COS cells [13].
  • Conversely, overexpression of active PKC epsilon stimulated Raf kinase activity in COS cells and overcame the inhibitory effects of dominant negative Ras in NIH 3T3 cells [13].
  • Cell fractionation localized both raf1CAAX and raf1(257L)CAAX to caveolae membranes independent of ras12V,37G expression; however, coexpression of ras12V,37G enhanced the activation of raf(257L)CAAX, but not raf1CAAX, as monitored by induction of cellular transformation, increased Raf kinase activity, and induction of activated MAP kinase [14].

Associations of Zhx2 with chemical compounds

  • In contrast, treatment of Raf-1 with a serine/threonine-specific phosphatase, protein phosphatase 1 (PP-1), resulted in a more modest decrease in Raf in vitro kinase activity, and this effect was prevented by okadaic acid [15].
  • The Raf protein kinases function downstream of Ras guanine nucleotide-binding proteins to transduce intracellular signals from growth factor receptors [13].
  • The Raf family proto-oncogenes encode cytoplasmic protein serine/threonine kinases which play a critical role in cell growth and development [16].
  • Evidence from studies in HeLa cells suggest that UVC regulates NF-kappa B activity via tyrosine kinases and activation of Ras and Raf kinase [17].
  • We provide evidence that Ras proteins regulate the activity of choline kinase through its direct effectors Ral-GDS and PI3K, while the Raf pathways seems to be not relevant in this process [18].

Regulatory relationships of Zhx2

  • RalGDS does not significantly enhance MAP kinase activation by activated Raf, suggesting that the cooperativity in focus formation is due to a distinct pathway acting downstream of Ras and parallel to Raf [19].
  • These data indicate that tyrosine phosphorylation of PLC-gamma 1 is not sufficient for growth induction in NIH3T3 cells and that Ras mediates signal transfer from activated membrane receptors to Raf kinases in the cytosol [20].

Other interactions of Zhx2

  • Raf inhibition substantially diminished the activities of Erks in v-raf-transformed cells but not in v-abl-transformed cells, indicating that v-abl can activate Erks by a Raf-1-independent pathway [21].
  • Complementation of defective colony-stimulating factor 1 receptor signaling and mitogenesis by Raf and v-Src [11].
  • Ksr is a kinase with similarities to the three conserved regions of Raf kinases, especially within the kinase domain [22].
  • These results are consistent with Raf kinases acting downstream of Ras, but not upstream of MAPK and RSK in insulin-signaling pathways leading to 3T3 L1 differentiation [23].
  • The Raf/MEK/ERK kinase cascade is pivotal in transmitting signals from membrane receptors to transcription factors that control gene expression culminating in the regulation of cell cycle progression [24].

Analytical, diagnostic and therapeutic context of Zhx2

  • The ability of oncogenes such as Raf and v-Src to regulate the expression of these proteins reveals new lines of communication between cytosolic signal transducers and the cell cycle machinery [11].
  • Ras, Raf and MEK inhibitors have been developed, and some of them are in advanced clinical trials [25].
  • Receptor ligation caused rapid inactivation of p21(ras), a decrease in Raf phosphorylation and in mitogen-activated protein kinase (MAPK) enzymatic activity, and G1 cell cycle arrest [26].


  1. Hereditary persistence of alpha-fetoprotein and H19 expression in liver of BALB/cJ mice is due to a retrovirus insertion in the Zhx2 gene. Perincheri, S., Dingle, R.W., Peterson, M.L., Spear, B.T. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  2. Lung-specific expression of active Raf kinase results in increased mortality of influenza A virus-infected mice. Olschläger, V., Pleschka, S., Fischer, T., Rziha, H.J., Wurzer, W., Stitz, L., Rapp, U.R., Ludwig, S., Planz, O. Oncogene (2004) [Pubmed]
  3. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Gollob, J.A., Wilhelm, S., Carter, C., Kelley, S.L. Semin. Oncol. (2006) [Pubmed]
  4. Bcl-2 determines susceptibility to induction of lung cancer by oncogenic CRaf. Fedorov, L.M., Tyrsin, O.Y., Papadopoulos, T., Camarero, G., Götz, R., Rapp, U.R. Cancer Res. (2002) [Pubmed]
  5. Use of human tissue to assess the oncogenic activity of melanoma-associated mutations. Chudnovsky, Y., Adams, A.E., Robbins, P.B., Lin, Q., Khavari, P.A. Nat. Genet. (2005) [Pubmed]
  6. Activation of the Raf-1 kinase cascade by coumermycin-induced dimerization. Farrar, M.A., Alberol-Ila, n.u.l.l., Perlmutter, R.M. Nature (1996) [Pubmed]
  7. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Kolch, W., Heidecker, G., Lloyd, P., Rapp, U.R. Nature (1991) [Pubmed]
  8. Rapid induction of heparin-binding epidermal growth factor/diphtheria toxin receptor expression by Raf and Ras oncogenes. McCarthy, S.A., Samuels, M.L., Pritchard, C.A., Abraham, J.A., McMahon, M. Genes Dev. (1995) [Pubmed]
  9. Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. Mikula, M., Schreiber, M., Husak, Z., Kucerova, L., Rüth, J., Wieser, R., Zatloukal, K., Beug, H., Wagner, E.F., Baccarini, M. EMBO J. (2001) [Pubmed]
  10. Hydrolysis of phosphatidylcholine couples Ras to activation of Raf protein kinase during mitogenic signal transduction. Cai, H., Erhardt, P., Troppmair, J., Diaz-Meco, M.T., Sithanandam, G., Rapp, U.R., Moscat, J., Cooper, G.M. Mol. Cell. Biol. (1993) [Pubmed]
  11. Complementation of defective colony-stimulating factor 1 receptor signaling and mitogenesis by Raf and v-Src. Aziz, N., Cherwinski, H., McMahon, M. Mol. Cell. Biol. (1999) [Pubmed]
  12. Activation of the Raf-1/MAP kinase cascade is not sufficient for Ras transformation of RIE-1 epithelial cells. Oldham, S.M., Clark, G.J., Gangarosa, L.M., Coffey, R.J., Der, C.J. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  13. Role of diacylglycerol-regulated protein kinase C isotypes in growth factor activation of the Raf-1 protein kinase. Cai, H., Smola, U., Wixler, V., Eisenmann-Tappe, I., Diaz-Meco, M.T., Moscat, J., Rapp, U., Cooper, G.M. Mol. Cell. Biol. (1997) [Pubmed]
  14. Physical association with ras enhances activation of membrane-bound raf (RafCAAX). Mineo, C., Anderson, R.G., White, M.A. J. Biol. Chem. (1997) [Pubmed]
  15. Interleukin 2 regulates Raf-1 kinase activity through a tyrosine phosphorylation-dependent mechanism in a T-cell line. Turner, B.C., Tonks, N.K., Rapp, U.R., Reed, J.C. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  16. Regulation of A-raf expression. Lee, J.E., Beck, T.W., Wojnowski, L., Rapp, U.R. Oncogene (1996) [Pubmed]
  17. Ras-independent activation of Rel-family transcription factors by UVB and TPA in cultured keratinocytes. Tobin, D., Nilsson, M., Toftgård, R. Oncogene (1996) [Pubmed]
  18. Regulation of choline kinase activity by Ras proteins involves Ral-GDS and PI3K. Ramírez de Molina, A., Penalva, V., Lucas, L., Lacal, J.C. Oncogene (2002) [Pubmed]
  19. A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. White, M.A., Vale, T., Camonis, J.H., Schaefer, E., Wigler, M.H. J. Biol. Chem. (1996) [Pubmed]
  20. Ras controls coupling of growth factor receptors and protein kinase C in the membrane to Raf-1 and B-Raf protein serine kinases in the cytosol. Troppmair, J., Bruder, J.T., App, H., Cai, H., Liptak, L., Szeberényi, J., Cooper, G.M., Rapp, U.R. Oncogene (1992) [Pubmed]
  21. Inhibition of the Raf-1 kinase by cyclic AMP agonists causes apoptosis of v-abl-transformed cells. Weissinger, E.M., Eissner, G., Grammer, C., Fackler, S., Haefner, B., Yoon, L.S., Lu, K.S., Bazarov, A., Sedivy, J.M., Mischak, H., Kolch, W. Mol. Cell. Biol. (1997) [Pubmed]
  22. Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Denouel-Galy, A., Douville, E.M., Warne, P.H., Papin, C., Laugier, D., Calothy, G., Downward, J., Eychène, A. Curr. Biol. (1998) [Pubmed]
  23. Dissociation between activation of Raf-1 kinase and the 42-kDa mitogen-activated protein kinase/90-kDa S6 kinase (MAPK/RSK) cascade in the insulin/Ras pathway of adipocytic differentiation of 3T3 L1 cells. Porras, A., Muszynski, K., Rapp, U.R., Santos, E. J. Biol. Chem. (1994) [Pubmed]
  24. Effects of the RAF/MEK/ERK and PI3K/AKT signal transduction pathways on the abrogation of cytokine-dependence and prevention of apoptosis in hematopoietic cells. Shelton, J.G., Steelman, L.S., Lee, J.T., Knapp, S.L., Blalock, W.L., Moye, P.W., Franklin, R.A., Pohnert, S.C., Mirza, A.M., McMahon, M., McCubrey, J.A. Oncogene (2003) [Pubmed]
  25. ERK and beyond: insights from B-Raf and Raf-1 conditional knockouts. Galabova-Kovacs, G., Kolbus, A., Matzen, D., Meissl, K., Piazzolla, D., Rubiolo, C., Steinitz, K., Baccarini, M. Cell Cycle (2006) [Pubmed]
  26. A G1 cell cycle arrest induced by ligands of the reovirus type 3 receptor is secondary to inactivation of p21ras and mitogen-activated protein kinase. Saragovi, H.U., Rebai, N., Di Guglielmo, G.M., Macleod, R., Sheng, J., Rubin, D.H., Greene, M.I. DNA Cell Biol. (1999) [Pubmed]
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