Browse > Article
http://dx.doi.org/10.14348/molcells.2018.2257

PPARα-Target Gene Expression Requires TIS21/BTG2 Gene in Liver of the C57BL/6 Mice under Fasting Condition  

Hong, Allen Eugene (Ajou Graduate School of medicine)
Ryu, Min Sook (BK Plus program, Department of Biomedical Sciences, Ajou University Graduate School of Medicine)
Kim, Seung Jun (R&D center, BioCore Co. Ltd.)
Hwang, Seung Yong (R&D center, BioCore Co. Ltd.)
Lim, In Kyoung (Ajou Graduate School of medicine)
Publication Information
Molecules and Cells / v.41, no.2, 2018 , pp. 140-149 More about this Journal
Abstract
The $TIS21^{/BTG2/PC3}$ gene belongs to the antiproliferative gene (APRO) family and exhibits tumor suppressive activity. However, here we report that TIS21 controls lipid metabolism, rather than cell proliferation, under fasting condition. Using microarray analysis, whole gene expression changes were investigated in liver of TIS21 knockout (TIS21-KO) mice after 20 h fasting and compared with wild type (WT). Peroxisome proliferator-activated receptor alpha ($PPAR{\alpha}$) target gene expression was almost absent in contrast to increased lipid synthesis in the TIS21-KO mice compared to WT mice. Immunohistochemistry with hematoxylin and eosin staining revealed that lipid deposition was focal in the TIS21-KO liver as opposed to the diffuse and homogeneous pattern in the WT liver after 24 h starvation. In addition, cathepsin E expression was over 10 times higher in the TIS21-KO liver than that in the WT, as opposed to the significant reduction of thioltransferase in both adult and fetal livers. At present, we cannot account for the role of cathepsin E. However, downregulation of glutaredoxin 2 thioltransferase expression might affect hypoxic damage in the TIS21-KO liver. We suggest that the $TIS21^{/BTG2}$ gene might be essential to maintain energy metabolism and reducing power in the liver under fasting condition.
Keywords
BTG2; fatty acid oxidation; liver metabolism; $PPAR{\alpha}$; starvation;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Lim, I.K. (2006). TIS21/BTG2/PC3 as a link between ageing and cancer: cell cycle regulator and endogenous cell death molecule. J. Cancer Res. Clin. Oncol. 132, 417-426.   DOI
2 Lim, I.K., Lee, M.S., Lee, S.H., Kim, N.K., Jou, I., Seo, J.-S., and Park, S.C. (1995). Differential expression of TIS21 and TIS1 genes in the various organs of Balb/c mice, thymic carcinoma tissues and human cancer cell lines. J. Cancer Res. Clin. Oncol. 121, 279-284.   DOI
3 Lim, S.-K., Choi, Y.W., Lim, I.K., and Park, T.J. (2012). BTG2 suppresses cancer cell migration through inhibition of Src-FAK signaling by downregulation of reactive oxygen species generation in mitochondria. Clin. Exp. Metastasis 29, 901-913.   DOI
4 Mao, B., Zhang, Z., and Wang, G. (2015). BTG2: A rising star of tumor suppressors. Int. J. Oncol. 46, 459-464.   DOI
5 Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T., and Ohsumi, Y. (2004). In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101-1111.   DOI
6 Mootha, V.K., Lindgren, C.M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstrale, M., and Laurila, E. (2003). PGC-$1{\alpha}$-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267-273.   DOI
7 Park, T.J., Kim, J.Y., Oh, S.P., Kang, S.Y., Kim, B.W., Wang, H.J., Song, K.Y., Kim, H.C., and Lim, I.K. (2008). TIS21 negatively regulates hepatocarcinogenesis by disruption of cyclin B1-Forkhead box M1 regulation loop. Hepatology 47, 1533-1543.   DOI
8 Newberry, E.P., Xie, Y., Kennedy, S., Han, X., Buhman, K.K., Luo, J., Gross, R.W., and Davidson, N.O. (2003). Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene. J. Biol. Chem. 278, 51664-51672.   DOI
9 Page, J.L., Strom, S.C., and Omiecinski, C.J. (2007). Regulation of the human cathepsin E gene by the constitutive androstane receptor. Arch. Biochem. Biophys. 467, 132-138.   DOI
10 Park, S., Lee, Y.J., Lee, H.-J., Seki, T., Hong, K.-H., Park, J., Beppu, H., Lim, I.K., Yoon, J.-W., and Li, E. (2004). B-cell translocation gene 2 (Btg2) regulates vertebral patterning by modulating bone morphogenetic protein/smad signaling. Mol. Cell. Biol. 24, 10256-10262.   DOI
11 Passeri, D., Marcucci, A., Rizzo, G., Billi, M., Panigada, M., Leonardi, L., Tirone, F., and Grignani, F. (2006). Btg2 enhances retinoic acidinduced differentiation by modulating histone H4 methylation and acetylation. Mol. Cell. Biol. 26, 5023-5032.   DOI
12 Rabinowitz, J.D., and White, E. (2010). Autophagy and metabolism. Science 330, 1344-1348.   DOI
13 Sundaramoorthy, S., Ryu, M.S., and Lim, I.K. (2013). B-cell translocation gene 2 mediates crosstalk between PI3K/Akt1 and NF${\kappa}B$ pathways which enhances transcription of MnSOD by accelerating I${\kappa}B$${\alpha}$ degradation in normal and cancer cells. Cell Commun. Signal. 11, 69.   DOI
14 Rakhshandehroo, M., Knoch, B., Muller, M., and Kersten, S. (2010). Peroxisome proliferator-activated receptor alpha target genes. PPAR Res. 2010.
15 Rouault, J.P., Falette, N., Guehenneux, F., Guillot, C., Rimokh, R., Wang, Q., Berthet, C., Moyret-Lalle, C., Savatier, P., Pain, B., et al. (1996). Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nat. Genet. 14, 482-486.   DOI
16 Schupp, M., Chen, F., Briggs, E.R., Rao, S., Pelzmann, H.J., Pessentheiner, A.R., Bogner-Strauss, J.G., Lazar, M.A., Baldwin, D., and Prokesch, A. (2013). Metabolite and transcriptome analysis during fasting suggest a role for the p53-Ddit4 axis in major metabolic tissues. BMC Genomics 14, 758.   DOI
17 Shannon, P., Markiel, A., Ozier, O., Baliga, N.S., Wang, J.T., Ramage, D., Amin, N., Schwikowski, B., and Ideker, T. (2003). Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498-2504.   DOI
18 Subramanian, A., Tamayo, P., Mootha, V.K., Mukherjee, S., Ebert, B.L., Gillette, M.A., Paulovich, A., Pomeroy, S.L., Golub, T.R., and Lander, E.S. (2005). Gene set enrichment analysis: a knowledgebased approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545-15550.   DOI
19 Terra, R., Luo, H., Qiao, X., and Wu, J. (2008). Tissue-specific expression of B-cell translocation gene 2 (BTG2) and its function in Tcell immune responses in a transgenic mouse model. Int. Immunol. 20, 317-326.   DOI
20 Wu, H., Xing, K., and Lou, M.F. (2010). Glutaredoxin 2 prevents H2O2-induced cell apoptosis by protecting complex I activity in the mitochondria. Biochim. Biophys. Acta -Bioenergetics 1797, 1705-1715.   DOI
21 Yamamoto, K., Kawakubo, T., Yasukochi, A., and Tsukuba, T. (2012). Emerging roles of cathepsin E in host defense mechanisms. Biochim. Biophys. Acta -Bioenergetics 1824, 105-112.   DOI
22 Zhang, F., Xu, X., Zhou, B., He, Z., and Zhai, Q. (2011). Gene expression profile change and associated physiological and pathological effects in mouse liver induced by fasting and refeeding. PloS one 6, e27553.   DOI
23 Kageyama, T., Tatematsu, M., Ichinose, M., Yahagi, N., Miki, K., Moriyama, A., and Yonezawa, S. (1998). Development-dependent expression of cathepsins d and e in various rat tissues, with special reference to the high expression of cathepsin e in fetal liver. Zool. Sci. 15, 517-523.
24 Kanehisa, M., Sato, Y., Kawashima, M., Furumichi, M., and Tanabe, M. (2016). KEGG as a reference resource for gene and protein annotation. Nucleic Acids Res. 44, D457-D462.   DOI
25 Kim, B.C., Ryu, M.S., Oh, S.P., and Lim, I.K. (2008). TIS21/BTG2 negatively regulates estradiol-stimulated expansion of hematopoietic stem cells by derepressing Akt phosphorylation and inhibiting mTOR signal transduction. Stem Cells 26, 2339-2348.   DOI
26 Kim, Y.-D., Im, S.-S., Oh, B.-C., Bae, J.-H., and Song, D.-K. (2014). Bcell Translocation Gene 2 regulates hepatic glucose homeostasis via induction of orphan nuclear receptor Nur77 in diabetic mouse model. Diabetes 63, 1870-1880   DOI
27 Li, C., Yu, S., Zhong, X., Wu, J., and Li, X. (2012). Transcriptome comparison between fetal and adult mouse livers: implications for circadian clock mechanisms. PloS one 7, e31292.   DOI
28 Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., and Uchiyama, Y. (2005). Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425-434.   DOI
29 Lee, Y.-H., Kim, H.-J., Lee, W.-Y., Kim, M.-J., Tark, D.-S., Cho, I.-S., and Sohn, H.-J. (2012). Gene expression profile of a persistently chronic wasting disease (CWD) prion-infected RK13 cell line. J. Prev. Veterinary Med. 36, 186-195.
30 Lee, J.M., Wagner, M., Xiao, R., Kim, K.H., Feng, D., Lazar, M.A., and Moore, D.D. (2014). Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516, 112-115.
31 Kanehisa, M., and Goto, S. (2000). KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27-30.   DOI
32 Choi, J., Jung, Y., Kim, J., Kim, H., and Lim, I. (2016). Inhibition of breast cancer invasion by TIS21/BTG2/Pc3-Akt1-Sp1-Nox4 pathway targeting actin nucleators, mDia genes. Oncogene 35, 83.   DOI
33 Fletcher, B., Lim, R., Varnum, B., Kujubu, D., Koski, R., and Herschman, H. (1991). Structure and expression of TIS21, a primary response gene induced by growth factors and tumor promoters. J. Biol. Chem. 266, 14511-14518.
34 Folch, J., Lees, M., and Sloane-Stanley, G. (1957). A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226, 497-509.
35 Bradbury, A., Possenti, R., Shooter, E.M., and Tirone, F. (1991). Molecular cloning of PC3, a putatively secreted protein whose mRNA is induced by nerve growth factor and depolarization. Proc. Natl. Acad. Sci. USA 88, 3353-3357.   DOI
36 Hakvoort, T.B., Moerland, P.D., Frijters, R., Sokolovic, A., Labruyere, W.T., Vermeulen, J.L., van Themaat, E.V.L., Breit, T.M., Wittink, F.R., and van Kampen, A.H. (2011). Interorgan coordination of the murine adaptive response to fasting. J. Biol. Chem. 286, 16332-16343.   DOI
37 Hu, X.-D., Meng, Q.-H., Xu, J.-Y., Jiao, Y., Ge, C.-M., Jacob, A., Wang, P., Rosen, E.M., and Fan, S. (2011). BTG2 is an LXXLLdependent co-repressor for androgen receptor transcriptional activity. Biochem. Biophys. Res. Commun. 404, 903-909.   DOI
38 Huang, D.W., Sherman, B.T., and Lempicki, R.A. (2008). Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1-13.
39 Huang, D.W., Sherman, B.T., and Lempicki, R.A. (2009). Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protocols 4, 44.   DOI
40 Hwang, S.-L., Kwon, O., Lee, S.J., Roh, S.-S., Kim, Y.D., and Choi, J.H. (2012). B-cell translocation gene-2 increases hepatic gluconeogenesis via induction of CREB. Biochem. Biophys. Res. Commun. 427, 801-805.   DOI
41 Choi, J.-A., and Lim, I.K. (2013). TIS21/BTG2 inhibits invadopodia formation by downregulating reactive oxygen species level in MDAMB-231 cells. J. Cancer Res. Clin. Oncol. 139, 1657-1665.   DOI
42 Cahill Jr, G.F. (2006). Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1-22.   DOI
43 Chlabicz, M., Gacko, M., Worowska, A., and Łapinski, R. (2011). Cathepsin E (EC 3.4. 23.34)-a review. Folia Histochem. Cytobiol. 49, 547-557.