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Gene Review

ZHX2  -  zinc fingers and homeoboxes 2

Homo sapiens

Synonyms: AFP regulator 1, AFR1, Alpha-fetoprotein regulator 1, KIAA0854, RAF, ...
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Disease relevance of ZHX2

  • Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas [1].
  • Thus, a fundamental switch in RAF isoform usage occurs when RAS is mutated in melanoma, and this occurs in the context of disrupted cAMP signaling [2].
  • In addition, abnormal expression of only three genes (RAN, ZHX-2, CHC1L) is associated with rapid relapses [3].

High impact information on ZHX2

  • In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation [1].
  • Melanocytes require the RAS/RAF/MEK/ERK and the cyclic AMP (cAMP) signaling pathways to maintain the fine balance between proliferation and differentiation [2].
  • While studying mechanisms of glomerular disease, rat ZHX3 was cloned from a down-regulated gene fragment; its cellular localization, DNA binding, and transcriptional repressor properties were characterized; and its ability to influence podocyte gene expression directly or via ZHX1 and ZHX2 was studied [4].
  • The recent demonstration of mutations in B-RAF and C-RAF in human tumors marked the return of RAF kinases to their roots as oncogenes [5].
  • RAF kinases entered the limelight when our understanding of the genetic nature of cancer was much less defined and the seminal importance of proto-oncogenes as components of intracellular signaling pathways was just beginning to be recognized [5].

Biological context of ZHX2


Anatomical context of ZHX2

  • By using bisulfite sequencing, we confirmed that hypermethylation of the 5' CpG island of ZHX2 occurred in some HCC and HepG2 cell lines but not in 6 normal liver tissue samples [8].

Physical interactions of ZHX2

  • Moreover, ZHX2 interacts with the activation domain of NF-YA [6].

Other interactions of ZHX2

  • Using a yeast two-hybrid system, a novel ubiquitous transcription factor ZHX2 as a ZHX1-interacting protein was cloned [6].
  • A 4.5-kb ZHX2 transcript, and three ZHX3 transcripts, 9.5-, 6.5- and 4.4-kb, are ubiquitously expressed, although their levels vary [7].
  • Promoter hypermethylation of a novel gene, ZHX2, in hepatocellular carcinoma [8].

Analytical, diagnostic and therapeutic context of ZHX2

  • Lastly, using an immunoprecipitation assay, we showed that ZHX2 intrinsically interacts with NF-YA in HEK-293 cells and that ZHX2 represses the promoter activity of the cdc25C gene stimulated by NF-Y in Drosophila Schneider line 2 cells [6].
  • Following the discovery of the v-RAF oncogene and the subsequent description of the c-RAF-1 gene by the group of Ulf Rapp, the last 20 years have seen the dissection of the signaling pathways in which RAF kinases function, and the cellular processes they control [5].


  1. AAL881, a Novel Small Molecule Inhibitor of RAF and Vascular Endothelial Growth Factor Receptor Activities, Blocks the Growth of Malignant Glioma. Sathornsumetee, S., Hjelmeland, A.B., Keir, S.T., McLendon, R.E., Batt, D., Ramsey, T., Yusuff, N., Rasheed, B.K., Kieran, M.W., Laforme, A., Bigner, D.D., Friedman, H.S., Rich, J.N. Cancer Res. (2006) [Pubmed]
  2. In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling. Dumaz, N., Hayward, R., Martin, J., Ogilvie, L., Hedley, D., Curtin, J.A., Bastian, B.C., Springer, C., Marais, R. Cancer Res. (2006) [Pubmed]
  3. Multiple myeloma. Harousseau, J.L., Shaughnessy, J., Richardson, P. Hematology / the Education Program of the American Society of Hematology. American Society of Hematology. Education Program. (2004) [Pubmed]
  4. ZHX proteins regulate podocyte gene expression during the development of nephrotic syndrome. Liu, G., Clement, L.C., Kanwar, Y.S., Avila-Casado, C., Chugh, S.S. J. Biol. Chem. (2006) [Pubmed]
  5. Back to the roots: the remarkable RAF oncogene story. Zebisch, A., Troppmair, J. Cell. Mol. Life Sci. (2006) [Pubmed]
  6. Zinc-fingers and homeoboxes (ZHX) 2, a novel member of the ZHX family, functions as a transcriptional repressor. Kawata, H., Yamada, K., Shou, Z., Mizutani, T., Yazawa, T., Yoshino, M., Sekiguchi, T., Kajitani, T., Miyamoto, K. Biochem. J. (2003) [Pubmed]
  7. The mouse zinc-fingers and homeoboxes (ZHX) family; ZHX2 forms a heterodimer with ZHX3. Kawata, H., Yamada, K., Shou, Z., Mizutani, T., Miyamoto, K. Gene (2003) [Pubmed]
  8. Promoter hypermethylation of a novel gene, ZHX2, in hepatocellular carcinoma. Lv, Z., Zhang, M., Bi, J., Xu, F., Hu, S., Wen, J. Am. J. Clin. Pathol. (2006) [Pubmed]
  9. Differential gene expression in auristatin PHE-treated Cryptococcus neoformans. Woyke, T., Berens, M.E., Hoelzinger, D.B., Pettit, G.R., Winkelmann, G., Pettit, R.K. Antimicrob. Agents Chemother. (2004) [Pubmed]
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