- Short Communication
ZFAT is a critical molecule for cell survival in mouse embryonic fibroblasts
Cellular & Molecular Biology Letters volume 16, pages 89–100 (2011)
ZFAT was originally identified as an immune-related transcriptional regulator containing 18 C2H2-type zinc-finger domains and one AT-hook. ZFAT is highly conserved among species and functions as an anti-apoptotic molecule in the lymphoblastic leukemia cell line, MOLT-4. We recently demonstrated that ZFAT is an essential molecule for hematopoietic differentiation in blood islands through the direct regulation of particular transcriptional factors, including Tal1, for endothelial cell assembly, and for the branch point formation of capillary-like structures. However, the molecular mechanisms underlying the anti-apoptotic function of ZFAT remain unknown. Here, we report that ZFAT knockdown by small interfering RNA induced apoptosis in mouse embryonic fibroblasts (MEFs). This response had been similarly observed for MOLT-4 cells. To explore the molecular mechanisms for ZFAT in anti-apoptotic function in both MEFs and MOLT-4 cells, microarray expression analysis and quantitative RT-PCR were done. Of interest was that Bcl-2 and Il6st were identified as commonly down-regulated genes by the depletion of ZFAT for both MEFs and MOLT-4 cells. These results suggest that ZFAT is a critical molecule for cell survival in MEFs and MOLT-4 cells at least in part through the regulation of the apoptosis involved in the BCL-2- and IL6st-mediated pathways. Further elucidation of the molecular functions for ZFAT might shed light on the cellular programs in the mesoderm-derived cells.
zinc-finger gene in autoimmune thyroid disease susceptibility region
Jacobson, E.M. and Tomer, Y. The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to the future. J. Autoimmun. 28 (2007) 85–98.
Sakai, K., Shirasawa, S., Ishikawa, N., Ito, K., Tamai, H., Kuma, K., Akamizu, T., Tanimura, M., Furugaki, K., Yamamoto, K. and Sasazuki, T. Identification of susceptibility loci for autoimmune thyroid disease to 5q31-q33 and Hashimoto’s thyroiditis to 8q23-q24 by multipoint affected sib-pair linkage analysis in Japanese. Hum. Mol. Genet. 10 (2001) 1379–1386.
Shirasawa, S., Harada, H., Furugaki, K., Akamizu, T., Ishikawa, N., Ito, K., Tamai, H., Kuma, K., Kubota, S., Hiratani, H., Tsuchiya, T., Baba, I., Ishikawa, M., Tanaka, M., Sakai, K., Aoki, M., Yamamoto, K. and Sasazuki, T. SNPs in the promoter of a B cell-specific antisense transcript, SAS-ZFAT, determine susceptibility to autoimmune thyroid disease. Hum. Mol. Genet. 13 (2004) 2221–2231.
Koyanagi, M., Nakabayashi, K., Fujimoto, T., Gu, N., Baba, I., Takashima, Y., Doi, K., Harada, H., Kato, N., Sasazuki, T. and Shirasawa, S. ZFAT expression in B and T lymphocytes and identification of ZFAT-regulated genes. Genomics 91 (2008) 451–457.
Fujimoto, T., Doi, K., Koyanagi, M., Tsunoda, T., Takashima, Y., Yoshida, Y., Sasazuki, T. and Shirasawa, S. ZFAT is an antiapoptotic molecule and critical for cell survival in MOLT-4 cells. FEBS Lett. 583 (2009) 568–572.
Tsunoda, T., Takashima, Y., Tanaka, Y., Fujimoto, T., Doi, K., Hirose, Y., Koyanagi, M., Yoshida, Y., Okamura, T., Kuroki, M., Sasazuki, T. and Shirasawa, S. Immune-related zinc finger gene ZFAT is an essential transcriptional regulator for hematopoietic differentiation in blood islands. Proc. Natl. Acad. Sci. USA 107 (2010) 14199–14204.
Yoshida, Y., Tsunoda, T., Takashima, Y., Fujimoto, T., Doi, K., Sasazuki, T., Kuroki, M., Iwasaki, A. and Shirasawa, S. ZFAT is essential for endothelial cell assembly and the branch point formation of capillary-like structures in an angiogenesis model. Cell. Mol. Biol. Lett. 15 (2010) 541–550.
Takeuchi, F., Nabika, T., Isono, M., Katsuya, T., Sugiyama, T., Yamaguchi, S., Kobayashi, S., Yamori, Y., Ogihara, T. and Kato, N. Evaluation of genetic loci influencing adult height in the Japanese population. J. Hum. Genet. 54 (2009) 749–752.
Comabella, M., Craig, D.W., Morcillo-Suarez, C., Rio, J., Navarro, A., Fernandez, M., Martin, R. and Montalban, X. Genome-wide scan of 500,000 single-nucleotide polymorphisms among responders and nonresponders to interferon beta therapy in multiple sclerosis. Arch. Neurol. 66 (2009) 972–978.
Chao, D.T. and Korsmeyer, S.J. BCL-2 family: regulators of cell death. Annu. Rev. Immunol. 16 (1998) 395–419.
Hirano, T., Nakajima, K. and Hibi, M. Signaling mechanisms through gp130: a model of the cytokine system. Cytokine Growth Factor Rev. 8 (1997) 241–252.
Fukada, T., Hibi, M., Yamanaka, Y., Takahashi-Tezuka, M., Fujitani, Y., Yamaguchi, T., Nakajima, K. and Hirano, T. Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis. Immunity 5 (1996) 449–460.
Peterson, T.R., Laplante, M., Thoreen, C.C., Sancak, Y., Kang, S.A., Kuehl, W.M., Gray, N.S. and Sabatini, D.M. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 137 (2009) 873–886.
Proud, C.G. Dynamic balancing: DEPTOR tips the scales. J. Mol. Cell. Biol. 1 (2009) 61–63.
Wang, E.S., Teruya-Feldstein, J., Wu, Y., Zhu, Z., Hicklin, D.J. and Moore, M.A. Targeting autocrine and paracrine VEGF receptor pathways inhibits human lymphoma xenografts in vivo. Blood 104 (2004) 2893–2902.
Santos, S.C. and Dias, S. Internal and external autocrine VEGF/KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. Blood 103 (2004) 3883–3889.
Lee, Y.K., Bone, N.D., Strege, A.K., Shanafelt, T.D., Jelinek, D.F. and Kay, N.E. VEGF receptor phosphorylation status and apoptosis is modulated by a green tea component, epigallocatechin-3-gallate (EGCG), in B-cell chronic lymphocytic leukemia. Blood 104 (2004) 788–794.
Bellamy, W.T., Richter, L., Sirjani, D., Roxas, C., Glinsmann-Gibson, B., Frutiger, Y., Grogan, T.M. and List, A.F. Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes. Blood 97 (2001) 1427–1434.
Das, B., Yeger, H., Tsuchida, R., Torkin, R., Gee, M.F., Thorner, P.S., Shibuya, M., Malkin, D. and Baruchel, S. A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxiainducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. Cancer Res. 65 (2005) 7267–7275.
Lee, T.H., Seng, S., Sekine, M., Hinton, C., Fu, Y., Avraham, H.K. and Avraham, S. Vascular endothelial growth factor mediates intracrine survival in human breast carcinoma cells through internally expressed VEGFR1/FLT1. PLoS Med. 4 (2007) e186.
Electronic supplementary material
About this article
Cite this article
Doi, K., Fujimoto, T., Koyanagi, M. et al. ZFAT is a critical molecule for cell survival in mouse embryonic fibroblasts. Cell Mol Biol Lett 16, 89–100 (2011). https://doi.org/10.2478/s11658-010-0041-1
- Transcription factor
- Gene expression