This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ross, S. E.
Right arrow Articles by MacDougald, O. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ross, S. E.
Right arrow Articles by MacDougald, O. A.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 1999, p. 8433-8441, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Glycogen Synthase Kinase 3 Is an Insulin-Regulated C/EBPalpha Kinase

Sarah E. Ross, Robin L. Erickson, Nahid Hemati, and Ormond A. MacDougald*

Department of Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622

Received 8 July 1999/Returned for modification 25 August 1999/Accepted 8 September 1999

CCAAT/enhancer binding protein alpha  (C/EBPalpha ) is a transcription factor involved in creating and maintaining the adipocyte phenotype. We have shown previously that insulin stimulates dephosphorylation of C/EBPalpha in 3T3-L1 adipocytes. Studies to identify the insulin-sensitive sites of phosphorylation reveal that a C/EBPalpha peptide (amino acids H215 to K250) is phosphorylated on T222, T226, and S230 in vivo. The context of these phosphoamino acids implicates glycogen synthase kinase 3 (GSK3), whose activity is known to be repressed in response to insulin, as a potential kinase for phosphorylation of T222 and T226. Accordingly, GSK3 phosphorylates the predicted region of C/EBPalpha on threonine in vitro, and GSK3 uses C/EBPalpha as a substrate in vivo. In addition, the effect of pharmacological agents on GSK3 activity correlates with regulation of C/EBPalpha phosphorylation. Treatment of 3T3-L1 adipocytes with the phosphatidylinositol 3-kinase inhibitor wortmannin results in phosphorylation of C/EBPalpha , whereas treatment with the GSK3 inhibitor lithium results in dephosphorylation of C/EBPalpha . Collectively, these data indicate that insulin stimulates dephosphorylation of C/EBPalpha on T222 and T226 through inactivation of GSK3. Since dephosphorylation of C/EBPalpha in response to lithium is blocked by okadaic acid, strong candidates for the T222 and T226 phosphatase are protein phosphatases 1 and 2a. Treatment of adipocytes with insulin alters the protease accessibility of widespread sites within the N terminus of C/EBPalpha , consistent with phosphorylation causing profound conformational changes. Finally, phosphorylation of C/EBPalpha and other substrates by GSK3 may be required for adipogenesis, since treatment of differentiating preadipocytes with lithium inhibits their conversion to adipocytes.

* Corresponding author. Mailing address: Department of Physiology, University of Michigan Medical School, 1301 E. Catherine Rd., Ann Arbor, MI 48109-0622. Phone: (734) 647-4880. Fax: (734) 936-8813. E-mail: macdouga{at}umich.edu.

Molecular and Cellular Biology, December 1999, p. 8433-8441, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Terrand, J., Bruban, V., Zhou, L., Gong, W., El Asmar, Z., May, P., Zurhove, K., Haffner, P., Philippe, C., Woldt, E., Matz, R. L., Gracia, C., Metzger, D., Auwerx, J., Herz, J., Boucher, P. (2009). LRP1 Controls Intracellular Cholesterol Storage and Fatty Acid Synthesis through Modulation of Wnt Signaling. J. Biol. Chem. 284: 381-388 [Abstract] [Full Text]  
  • Wilson, W. III, Baldwin, A. S. (2008). Maintenance of Constitutive I{kappa}B Kinase Activity by Glycogen Synthase Kinase-3{alpha}/{beta} in Pancreatic Cancer. Cancer Res. 68: 8156-8163 [Abstract] [Full Text]  
  • Iida, S., Watanabe-Fukunaga, R., Nagata, S., Fukunaga, R. (2008). Essential role of C/EBPalpha in G-CSF-induced transcriptional activation and chromatin modification of myeloid-specific genes.. GENES CELLS 13: 313-327 [Abstract] [Full Text]  
  • Buitenhuis, M., Verhagen, L. P., van Deutekom, H. W. M., Castor, A., Verploegen, S., Koenderman, L., Jacobsen, S.-E. W., Coffer, P. J. (2008). Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis. Blood 111: 112-121 [Abstract] [Full Text]  
  • Barillas, R., Friehs, I., Cao-Danh, H., Martinez, J. F., del Nido, P. J. (2007). Inhibition of Glycogen Synthase Kinase-3{beta} Improves Tolerance to Ischemia in Hypertrophied Hearts. Ann. Thorac. Surg. 84: 126-133 [Abstract] [Full Text]  
  • Liu, J., Martin, H., Shamay, M., Woodard, C., Tang, Q.-Q., Hayward, S. D. (2007). Kaposi's Sarcoma-Associated Herpesvirus LANA Protein Downregulates Nuclear Glycogen Synthase Kinase 3 Activity and Consequently Blocks Differentiation. J. Virol. 81: 4722-4731 [Abstract] [Full Text]  
  • Tullai, J. W., Chen, J., Schaffer, M. E., Kamenetsky, E., Kasif, S., Cooper, G. M. (2007). Glycogen Synthase Kinase-3 Represses Cyclic AMP Response Element-binding Protein (CREB)-targeted Immediate Early Genes in Quiescent Cells. J. Biol. Chem. 282: 9482-9491 [Abstract] [Full Text]  
  • Datta, J., Majumder, S., Kutay, H., Motiwala, T., Frankel, W., Costa, R., Cha, H. C., MacDougald, O. A., Jacob, S. T., Ghoshal, K. (2007). Metallothionein Expression Is Suppressed in Primary Human Hepatocellular Carcinomas and Is Mediated through Inactivation of CCAAT/Enhancer Binding Protein {alpha} by Phosphatidylinositol 3-Kinase Signaling Cascade. Cancer Res. 67: 2736-2746 [Abstract] [Full Text]  
  • Ciaraldi, T. P., Oh, D. K., Christiansen, L., Nikoulina, S. E., Kong, A. P. S., Baxi, S., Mudaliar, S., Henry, R. R. (2006). Tissue-specific expression and regulation of GSK-3 in human skeletal muscle and adipose tissue. Am. J. Physiol. Endocrinol. Metab. 291: E891-E898 [Abstract] [Full Text]  
  • Qiao, L., MacDougald, O. A., Shao, J. (2006). CCAAT/Enhancer-binding Protein {alpha} Mediates Induction of Hepatic Phosphoenolpyruvate Carboxykinase by p38 Mitogen-activated Protein Kinase. J. Biol. Chem. 281: 24390-24397 [Abstract] [Full Text]  
  • Xu, Y., Zhou, Y. L., Luo, W., Zhu, Q.-S., Levy, D., MacDougald, O. A., Snead, M. L. (2006). NF-Y and CCAAT/Enhancer-binding Protein {alpha} Synergistically Activate the Mouse Amelogenin Gene. J. Biol. Chem. 281: 16090-16098 [Abstract] [Full Text]  
  • Gustafson, B., Smith, U. (2006). Cytokines Promote Wnt Signaling and Inflammation and Impair the Normal Differentiation and Lipid Accumulation in 3T3-L1 Preadipocytes. J. Biol. Chem. 281: 9507-9516 [Abstract] [Full Text]  
  • Zhao, X., Zhuang, S., Chen, Y., Boss, G. R., Pilz, R. B. (2005). Cyclic GMP-dependent Protein Kinase Regulates CCAAT Enhancer-binding Protein {beta} Functions through Inhibition of Glycogen Synthase Kinase-3. J. Biol. Chem. 280: 32683-32692 [Abstract] [Full Text]  
  • Johnson, P. F. (2005). Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J. Cell Sci. 118: 2545-2555 [Abstract] [Full Text]  
  • Williamson, E. A., Williamson, I. K., Chumakov, A. M., Friedman, A. D., Koeffler, H. P. (2005). CCAAT/enhancer binding protein {epsilon}: changes in function upon phosphorylation by p38 MAP kinase. Blood 105: 3841-3847 [Abstract] [Full Text]  
  • Gillio-Meina, C., Hui, Y. Y., LaVoie, H. A. (2005). Expression of CCAAT/Enhancer Binding Proteins Alpha and Beta in the Porcine Ovary and Regulation in Primary Cultures of Granulosa Cells. Biol. Reprod. 72: 1194-1204 [Abstract] [Full Text]  
  • MacAulay, K., Blair, A. S., Hajduch, E., Terashima, T., Baba, O., Sutherland, C., Hundal, H. S. (2005). Constitutive Activation of GSK3 Down-regulates Glycogen Synthase Abundance and Glycogen Deposition in Rat Skeletal Muscle Cells. J. Biol. Chem. 280: 9509-9518 [Abstract] [Full Text]  
  • Wang, G.-L., Timchenko, N. A. (2005). Dephosphorylated C/EBP{alpha} Accelerates Cell Proliferation through Sequestering Retinoblastoma Protein. Mol. Cell. Biol. 25: 1325-1338 [Abstract] [Full Text]  
  • Haugen, F., Zahid, N., Dalen, K. T., Hollung, K., Nebb, H. I., Drevon, C. A. (2005). Resistin expression in 3T3-L1 adipocytes is reduced by arachidonic acid. J. Lipid Res. 46: 143-153 [Abstract] [Full Text]  
  • Kim, K. H., Song, M. J., Yoo, E. J., Choe, S. S., Park, S. D., Kim, J. B. (2004). Regulatory Role of Glycogen Synthase Kinase 3 for Transcriptional Activity of ADD1/SREBP1c. J. Biol. Chem. 279: 51999-52006 [Abstract] [Full Text]  
  • Lagace, D. C., McLeod, R. S., Nachtigal, M. W. (2004). Valproic Acid Inhibits Leptin Secretion and Reduces Leptin Messenger Ribonucleic Acid Levels in Adipocytes. Endocrinology 145: 5493-5503 [Abstract] [Full Text]  
  • Choi, J.-H., Hur, J., Yoon, C.-H., Kim, J.-H., Lee, C.-S., Youn, S.-W., Oh, I.-Y., Skurk, C., Murohara, T., Park, Y.-B., Walsh, K., Kim, H.-S. (2004). Augmentation of Therapeutic Angiogenesis Using Genetically Modified Human Endothelial Progenitor Cells with Altered Glycogen Synthase Kinase-3{beta} Activity. J. Biol. Chem. 279: 49430-49438 [Abstract] [Full Text]  
  • Tullai, J. W., Schaffer, M. E., Mullenbrock, S., Kasif, S., Cooper, G. M. (2004). Identification of Transcription Factor Binding Sites Upstream of Human Genes Regulated by the Phosphatidylinositol 3-Kinase and MEK/ERK Signaling Pathways. J. Biol. Chem. 279: 20167-20177 [Abstract] [Full Text]  
  • Lagace, D. C., Nachtigal, M. W. (2004). Inhibition of Histone Deacetylase Activity by Valproic Acid Blocks Adipogenesis. J. Biol. Chem. 279: 18851-18860 [Abstract] [Full Text]  
  • Wang, G.-L., Iakova, P., Wilde, M., Awad, S., Timchenko, N. A. (2004). Liver tumors escape negative control of proliferation via PI3K/Akt-mediated block of C/EBP{alpha} growth inhibitory activity. Genes Dev. 18: 912-925 [Abstract] [Full Text]  
  • Ross, S. E., Radomska, H. S., Wu, B., Zhang, P., Winnay, J. N., Bajnok, L., Wright, W. S., Schaufele, F., Tenen, D. G., MacDougald, O. A. (2004). Phosphorylation of C/EBP{alpha} Inhibits Granulopoiesis. Mol. Cell. Biol. 24: 675-686 [Abstract] [Full Text]  
  • D'Alo', F., Johansen, L. M., Nelson, E. A., Radomska, H. S., Evans, E. K., Zhang, P., Nerlov, C., Tenen, D. G. (2003). The amino terminal and E2F interaction domains are critical for C/EBP{alpha}-mediated induction of granulopoietic development of hematopoietic cells. Blood 102: 3163-3171 [Abstract] [Full Text]  
  • Kennell, J. A., O'Leary, E. E., Gummow, B. M., Hammer, G. D., MacDougald, O. A. (2003). T-Cell Factor 4N (TCF-4N), a Novel Isoform of Mouse TCF-4, Synergizes with {beta}-Catenin To Coactivate C/EBP{alpha} and Steroidogenic Factor 1 Transcription Factors. Mol. Cell. Biol. 23: 5366-5375 [Abstract] [Full Text]  
  • Park, K.-W., Yang, H.-M., Youn, S.-W., Yang, H.-J., Chae, I.-H., Oh, B.-H., Lee, M.-M., Park, Y.-B., Choi, Y.-S., Kim, H.-S., Walsh, K. (2003). Constitutively Active Glycogen Synthase Kinase-3{beta} Gene Transfer Sustains Apoptosis, Inhibits Proliferation of Vascular Smooth Muscle Cells, and Reduces Neointima Formation After Balloon Injury in Rats. Arterioscler. Thromb. Vasc. Bio. 23: 1364-1369 [Abstract] [Full Text]  
  • Shim, M., Smart, R. C. (2003). Lithium Stabilizes the CCAAT/Enhancer-binding Protein {alpha} (C/EBP{alpha}) through a Glycogen Synthase Kinase 3 (GSK3)-independent Pathway Involving Direct Inhibition of Proteasomal Activity. J. Biol. Chem. 278: 19674-19681 [Abstract] [Full Text]  
  • Subramanian, L., Benson, M. D., Iniguez-Lluhi, J. A. (2003). A Synergy Control Motif within the Attenuator Domain of CCAAT/Enhancer-binding Protein alpha Inhibits Transcriptional Synergy through Its PIASy-enhanced Modification by SUMO-1 or SUMO-3. J. Biol. Chem. 278: 9134-9141 [Abstract] [Full Text]  
  • Schuster, C., Forster, K., Dierks, H., Elsasser, A., Behre, G., Simon, N., Danhauser-Riedl, S., Hallek, M., Warmuth, M. (2003). The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate. Blood 101: 655-663 [Abstract] [Full Text]  
  • Efimova, T., Deucher, A., Kuroki, T., Ohba, M., Eckert, R. L. (2002). Novel Protein Kinase C Isoforms Regulate Human Keratinocyte Differentiation by Activating a p38delta Mitogen-activated Protein Kinase Cascade That Targets CCAAT/Enhancer-binding Protein alpha. J. Biol. Chem. 277: 31753-31760 [Abstract] [Full Text]  
  • Ross, S. E., Erickson, R. L., Gerin, I., DeRose, P. M., Bajnok, L., Longo, K. A., Misek, D. E., Kuick, R., Hanash, S. M., Atkins, K. B., Andresen, S. M., Nebb, H. I., Madsen, L., Kristiansen, K., MacDougald, O. A. (2002). Microarray Analyses during Adipogenesis: Understanding the Effects of Wnt Signaling on Adipogenesis and the Roles of Liver X Receptor {alpha} in Adipocyte Metabolism. Mol. Cell. Biol. 22: 5989-5999 [Abstract] [Full Text]  
  • Behre, G., Singh, S. M., Liu, H., Bortolin, L. T., Christopeit, M., Radomska, H. S., Rangatia, J., Hiddemann, W., Friedman, A. D., Tenen, D. G. (2002). Ras Signaling Enhances the Activity of C/EBPalpha to Induce Granulocytic Differentiation by Phosphorylation of Serine 248. J. Biol. Chem. 277: 26293-26299 [Abstract] [Full Text]  
  • Nikoulina, S. E., Ciaraldi, T. P., Mudaliar, S., Carter, L., Johnson, K., Henry, R. R. (2002). Inhibition of Glycogen Synthase Kinase 3 Improves Insulin Action and Glucose Metabolism in Human Skeletal Muscle. Diabetes 51: 2190-2198 [Abstract] [Full Text]  
  • Schwabe, R. F., Brenner, D. A. (2002). Role of glycogen synthase kinase-3 in TNF-alpha -induced NF-kappa B activation and apoptosis in hepatocytes. Am. J. Physiol. Gastrointest. Liver Physiol. 283: G204-G211 [Abstract] [Full Text]  
  • Hardt, S. E., Sadoshima, J. (2002). Glycogen Synthase Kinase-3{beta}: A Novel Regulator of Cardiac Hypertrophy and Development. Circ. Res. 90: 1055-1063 [Abstract] [Full Text]  
  • Acquaah-Mensah, G. K., Kehrer, J. P., Leslie, S. W. (2002). In Utero Ethanol Suppresses Cerebellar Activator Protein-1 and Nuclear Factor-kappa B Transcriptional Activation in a Rat Fetal Alcohol Syndrome Model. J. Pharmacol. Exp. Ther. 301: 277-283 [Abstract] [Full Text]  
  • Berry, F. B., Saleem, R. A., Walter, M. A. (2002). FOXC1 Transcriptional Regulation Is Mediated by N- and C-terminal Activation Domains and Contains a Phosphorylated Transcriptional Inhibitory Domain. J. Biol. Chem. 277: 10292-10297 [Abstract] [Full Text]  
  • Bostik, P., Wu, P., Dodd, G. L., Villinger, F., Mayne, A. E., Bostik, V., Grimm, B. D., Robinson, D., Kung, H.-J., Ansari, A. A. (2001). Identification of Protein Kinases Dysregulated in CD4+ T Cells in Pathogenic versus Apathogenic Simian Immunodeficiency Virus Infection. J. Virol. 75: 11298-11306 [Abstract] [Full Text]  
  • Pedersen, T. A., Kowenz-Leutz, E., Leutz, A., Nerlov, C. (2001). Cooperation between C/EBPalpha TBP/TFIIB and SWI/SNF recruiting domains is required for adipocyte differentiation. Genes Dev. 15: 3208-3216 [Abstract] [Full Text]  
  • Shiina, H., Igawa, M., Urakami, S., Shigeno, K., Yoneda, T., Terashima, M., Deguchi, M., Ribeiro-Filho, L., Dahiya, R. (2001). Alterations of {beta}- and {gamma}-Catenin in N-Butyl-N-(-4-hydroxybutyl)nitrosamine-induced Murine Bladder Cancer. Cancer Res. 61: 7101-7109 [Abstract] [Full Text]  
  • Lochhead, P. A., Coghlan, M., Rice, S. Q.J., Sutherland, C. (2001). Inhibition of GSK-3 Selectively Reduces Glucose-6-Phosphatase and Phosphoenolpyruvate Carboxykinase Gene Expression. Diabetes 50: 937-946 [Abstract] [Full Text]  
  • Ross, S. E., Hemati, N., Longo, K. A., Bennett, C. N., Lucas, P. C., Erickson, R. L., MacDougald, O. A. (2000). Inhibition of Adipogenesis by Wnt Signaling. Science 289: 950-953 [Abstract] [Full Text]  
  • Kolligs, F. T., Kolligs, B., Hajra, K. M., Hu, G., Tani, M., Cho, K. R., Fearon, E. R. (2000). gamma -Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta -catenin. Genes Dev. 14: 1319-1331 [Abstract] [Full Text]  
  • Morisco, C., Zebrowski, D., Condorelli, G., Tsichlis, P., Vatner, S. F., Sadoshima, J. (2000). The Akt-Glycogen Synthase Kinase 3beta Pathway Regulates Transcription of Atrial Natriuretic Factor Induced by beta -Adrenergic Receptor Stimulation in Cardiac Myocytes. J. Biol. Chem. 275: 14466-14475 [Abstract] [Full Text]  
  • Dashti, S. R., Efimova, T., Eckert, R. L. (2001). MEK7-dependent Activation of p38 MAP Kinase in Keratinocytes. J. Biol. Chem. 276: 8059-8063 [Abstract] [Full Text]  
  • Piwien-Pilipuk, G., Van Mater, D., Ross, S. E., MacDougald, O. A., Schwartz, J. (2001). Growth Hormone Regulates Phosphorylation and Function of CCAAT/Enhancer-binding Protein beta by Modulating Akt and Glycogen Synthase Kinase-3. J. Biol. Chem. 276: 19664-19671 [Abstract] [Full Text]  
  • Erickson, R. L., Hemati, N., Ross, S. E., MacDougald, O. A. (2001). p300 Coactivates the Adipogenic Transcription Factor CCAAT/Enhancer-binding Protein alpha. J. Biol. Chem. 276: 16348-16355 [Abstract] [Full Text]  
  • Szanto, I., Kahn, C. R. (2000). Selective interaction between leptin and insulin signaling pathways in a hepatic cell line. Proc. Natl. Acad. Sci. USA 97: 2355-2360 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»