Download PDF
Horm Metab Res 2003; 35(11/12): 763-770
DOI: 10.1055/s-2004-814148
Original
© Georg Thieme Verlag Stuttgart · New York

Insulin-like Growth Factor-I Suppresses Degradation of the Pro-survival Transcription Factor Myocyte Enhancer Factor 2D (MEF2D) During Neuronal Apoptosis

B.  D.  Butts1 , D.  A.  Linseman1 , S.  S.  Le1 , T.  A.  Laessig1 , K.  A.  Heidenreich1
  • 1Department of Pharmacology, University of Colorado Health Sciences Center, and the Denver Veterans Affairs Medical Center, Denver, CO 80262, USA
Further Information

Publication History

Received 30 August 2003

Accepted after Revision 22 October 2003

Publication Date:
07 January 2004 (online)

Also available at
    Permissions and Reprints

Abstract

Cultured rat cerebellar granule neurons (CGNs) require depolarization-mediated calcium influx for survival. Calcium regulates the activity of the pro-survival transcription factor, myocyte enhancer factor 2D (MEF2D). MEF2D is hyperphosphorylated and degraded in CGNs undergoing apoptosis induced by lowering the extracellular potassium concentration from 25 mM to 5 mM. Since insulin-like growth factor-I (IGF-I) is known to protect CGNs from apoptotic cell death, we investigated the effects of IGF-I on MEF2D processing during apoptosis. IGF-I administered during the apoptotic insult did not prevent the hyperphosphorylation of MEF2D and consequential loss of DNA binding. However, IGF-I significantly blocked the degradation of MEF2D. Furthermore, IGF-I had no effect on the initial loss of MEF2 transcriptional activity following hyperphosphorylation, but the recovery of MEF2 activity following restoration of intracellular calcium was significantly increased by IGF-I. We conclude that IGF-I blocks the degradation of MEF2D and enhances recovery of MEF2 activity by protecting MEF2D from caspase-dependent cleavage during apoptosis. These results suggest that IGF-I can prolong the time of commitment to irreversible cell death and enhance the recovery of neurons subjected to an acute apoptotic stimulus by preserving the activity of the pro-survival factor MEF2D.

Key words

Cerebellar granule neurons - Neurodegeneration - Programmed cell death - Caspases - Signal transduction

References

  • 1 Stewart C E, Rotwein P. Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors.  Physiol Rev. 1996;  76 1005-1026
    PubMedSearch in Google Scholar
  • 2 D'Mello S R, Borodezt K, Soltoff S P. Insulin-like growth factor and potassium depolarization maintain neuronal survival by distinct pathways: possible involvement of PI 3-kinase in IGF-1 signaling.  J Neurosci. 1997;  17 1548-1560
    PubMedSearch in Google Scholar
  • 3 Lin X, Bulleit R F. Insulin-like growth factor I (IGF-I) is a critical trophic factor for developing cerebellar granule cells.  Brain Res Dev Brain Res. 1997;  99 234-242
    PubMedSearch in Google Scholar
  • 4 Vincent A M, Feldman E L. Control of cell survival by IGF signaling pathways.  Growth Horm IGF Res. 2002;  12 193-197
    PubMedSearch in Google Scholar
  • 5 Dudek H, Datta S R, Franke T F, Birnbaum M J, Yao R, Cooper G M, Segal R A, Kaplan D R, Greenberg M E. Regulation of neuronal survival by the serine-threonine protein kinase Akt.  Science. 1997;  275 661-665
    CrossrefPubMedSearch in Google Scholar
  • 6 Neri L M, Borgatti P, Capitani S, Martelli A M. The nuclear phosphoinositide 3-kinase/AKT pathway: a new second messenger system.  Biochim Biophys Acta. 2002;  1584 73-80
    PubMedSearch in Google Scholar
  • 7 Chang F, Lee J T, Navolanic P M, Steelman L S, Shelton J G, Blalock W L, Franklin R A, McCubrey J A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy.  Leukemia. 2003;  17 590-603
    CrossrefPubMedSearch in Google Scholar
  • 8 Linseman D A, Phelps R A, Bouchard R J, Le S S, Laessig T A, McClure M L, Heidenreich K A. Insulin-like growth factor-I blocks Bcl-2 interacting mediator of cell death (Bim) induction and intrinsic death signaling in cerebellar granule neurons.  J Neurosci. 2002;  22 9287-9297
    PubMedSearch in Google Scholar
  • 9 Zhong J, Deng J, Ghetti B, Lee W H. Inhibition of insulin-like growth factor I activity contributes to the premature apoptosis of cerebellar granule neuron in weaver mutant mice: in vitro analysis.  J Neurosci Res. 2002;  70 36-45
    CrossrefPubMedSearch in Google Scholar
  • 10 Barber A J, Nakamura M, Wolpert E B, Reiter C E, Seigel G M, Antonetti D A, Gardner T W. Insulin rescues retinal neurons from apoptosis by a phosphatidylinositol 3-kinase/Akt-mediated mechanism that reduces the activation of caspase-3.  J Biol Chem. 2001;  276 32 814-32 821
    PubMedSearch in Google Scholar
  • 11 Heck S, Lezoualc'h F, Engert S, Behl C. Insulin-like growth factor-1-mediated neuroprotection against oxidative stress is associated with activation of nuclear factor kappaB.  J Biol Chem. 1999;  274 9828-9835
    CrossrefPubMedSearch in Google Scholar
  • 12 Robinson L J, Leitner W, Draznin B, Heidenreich K A. Evidence that p21ras mediates the neurotrophic effects of insulin and insulin-like growth factor I in chick forebrain neurons.  Endocrinology. 1994;  135 2568-2573
    CrossrefPubMedSearch in Google Scholar
  • 13 Begum N, Robinson L J, Draznin B, Heidenreich K A. Protein phosphatase-1 and -2a activities in cultured fetal chick neurons: differential regulation by insulin and insulin-like growth factor-I.  Endocrinology. 1993;  133 2085-2090
    CrossrefPubMedSearch in Google Scholar
  • 14 Mohan S, Baylink D J. IGF-binding proteins are multifunctional and act via IGF-dependent and -independent mechanisms.  J Endocrinol. 2002;  175 19-31
    CrossrefPubMedSearch in Google Scholar
  • 15 Firth S M, Baxter R C. Cellular actions of the insulin-like growth factor binding proteins.  Endocr Rev. 2002;  23 824-854
    CrossrefPubMedSearch in Google Scholar
  • 16 Fizazi K, Yang J, Peleg S, Sikes C R, Kreimann E L, Daliani D, Olive M, Raymond K A, Janus T J, Logothetis C J, Karsenty G, Navone N M. Prostate cancer cells-osteoblast interaction shifts expression of growth/survival-related genes in prostate cancer and reduces expression of osteoprotegerin in osteoblasts.  Clin Cancer Res. 2003;  9 2587-2597
    PubMedSearch in Google Scholar
  • 17 Parker A, Cheville J C, Lohse C, Cerhan J R, Blute M L. Expression of insulin-like growth factor I receptor and survival in patients with clear cell renal cell carcinoma.  J Urol. 2003;  170 420-424
    PubMedSearch in Google Scholar
  • 18 Krystal G W, Sulanke G, Litz J. Inhibition of phosphatidylinositol 3-kinase-Akt signaling blocks growth, promotes apoptosis, and enhances sensitivity of small cell lung cancer cells to chemotherapy.  Mol Cancer Ther. 2002;  1 913-922
    PubMedSearch in Google Scholar
  • 19 Komninou D, Ayonote A, Richie J P Jr, Rigas B. Insulin resistance and its contribution to colon carcinogenesis.  Exp Biol Med (Maywood). 2003;  228 396-405
    PubMedSearch in Google Scholar
  • 20 Marshman E, Streuli C H. Insulin-like growth factors and insulin-like growth factor binding proteins in mammary gland function.  Breast Cancer Res. 2002;  4 231-239
    CrossrefPubMedSearch in Google Scholar
  • 21 Singleton J R, Randolph A E, Feldman E L. Insulin-like growth factor I receptor prevents apoptosis and enhances neuroblastoma tumorigenesis.  Cancer Res. 1996;  56 4522-4529
    PubMedSearch in Google Scholar
  • 22 LeRoith D, Roberts C T Jr. The insulin-like growth factor system and cancer.  Cancer Lett. 2003;  195 127-137
    CrossrefPubMedSearch in Google Scholar
  • 23 Dore S, Kar S, Quirion R. Rediscovering an old friend, IGF-I: potential use in the treatment of neurodegenerative diseases.  Trends Neurosci. 1997;  20 326-331
    CrossrefPubMedSearch in Google Scholar
  • 24 Azcoitia I, Doncarlos L L, Garcia-Segura L M. Estrogen and brain vulnerability.  Neurotox Res. 2002;  4 235-245
    PubMedSearch in Google Scholar
  • 25 Trejo J L, Carro E, Nunez A, Torres-Aleman I. Sedentary life impairs self-reparative processes in the brain: the role of serum insulin-like growth factor-I.  Rev Neurosci. 2002;  13 365-374
    CrossrefPubMedSearch in Google Scholar
  • 26 Dik M G, Pluijm S M, Jonker C, Deeg D J, Lomecky M Z, Lips P. Insulin-like growth factor I (IGF-I) and cognitive decline in older persons.  Neurobiol Aging. 2003;  24 573-581
    CrossrefPubMedSearch in Google Scholar
  • 27 D'Ercole A J, Ye P, O'Kusky J R. Mutant mouse models of insulin-like growth factor actions in the central nervous system.  Neuropeptides. 2002;  36 209-220
    CrossrefPubMedSearch in Google Scholar
  • 28 Garofalo R S. Genetic analysis of insulin signaling in Drosophila. .  Trends Endocrinol Metab. 2002;  13 156-162
    PubMedSearch in Google Scholar
  • 29 Linseman D A, McClure M L, Bouchard R J, Laessig T A, Ahmadi F A, Heidenreich K A. Suppression of death receptor signaling in cerebellar Purkinje neurons protects neighboring granule neurons from apoptosis via an insulin-like growth factor I-dependent mechanism.  J Biol Chem. 2002;  277 24 546-2453
    PubMedSearch in Google Scholar
  • 30 Li M, Linseman D A, Allen M P, Meintzer M K, Wang X, Laessig T, Wierman M E, Heidenreich K A. Myocyte enhancer factor 2A and 2D undergo phosphorylation and caspase-mediated degradation during apoptosis of rat cerebellar granule neurons.  J Neurosci. 2001;  21 6544-6552
    PubMedSearch in Google Scholar
  • 31 Allen M P, Xu M, Linseman D A, Pawlowski J E, Bokoch G M, Heidenreich K A, Wierman M E. Adhesion-related kinase repression of gonadotropin-releasing hormone gene expression requires Rac activation of the extracellular signal-regulated kinase pathway.  J Biol Chem. 2002;  277 38 133-38 140
    PubMedSearch in Google Scholar
  • 32 Linseman D A, Cornejo B J, Le S S, Meintzer M K, Laessig T A, Bouchard R J, Heidenreich K A. A myocyte enhancer factor 2D (MEF2D) kinase activated during neuronal apoptosis is a novel target inhibited by lithium.  J Neurochem. 2003;  85 1488-1499
    CrossrefPubMedSearch in Google Scholar
  • 33 Black B L, Olson E N. Transcriptional control of muscle development by myocyte enhancer factor-2 (MEF2) proteins.  Annu Rev Cell Dev Biol. 1998;  14 167-196
    CrossrefPubMedSearch in Google Scholar
  • 34 Yu Y T, Breitbart R E, Smoot L B, Lee Y, Mahdavi V, Nadal-Ginard B. Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors.  Genes Dev. 1992;  6 1783-1798
    PubMedSearch in Google Scholar
  • 35 Mao Z, Bonni A, Xia F, Nadal-Vicens M, Greenberg M E. Neuronal activity-dependent cell survival mediated by transcription factor MEF2.  Science. 1999;  286 785-790
    CrossrefPubMedSearch in Google Scholar
  • 36 McKinsey T A, Zhang C L, Olson E N. MEF2: a calcium-dependent regulator of cell division, differentiation and death.  Trends Biochem Sci. 2002;  27 40-47
    CrossrefPubMedSearch in Google Scholar
  • 37 Lemercier C, Verdel A, Galloo B, Curtet S, Brocard M P, Khochbin S. mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity.  J Biol Chem. 2000;  275 15 594-15 599
    PubMedSearch in Google Scholar
  • 38 Li M, Wang X, Meintzer M K, Laessig T, Birnbaum M J, Heidenreich K A. Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta.  Mol Cell Biol. 2000;  20 9356-9363
    CrossrefPubMedSearch in Google Scholar
  • 39 Amacher S L, Buskin J N, Hauschka S D. Multiple regulatory elements contribute differentially to muscle creatine kinase enhancer activity in skeletal and cardiac muscle.  Mol Cell Biol. 1993;  13 2753-2764
    PubMedSearch in Google Scholar
  • 40 D'Mello S R, Galli C, Ciotti T, Calissano P. Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP.  Proc Natl Acad Sci USA. 1993;  90 10 989-10 993
    PubMedSearch in Google Scholar
  • 41 Mao Z, Wiedmann M. Calcineurin enhances MEF2 DNA binding activity in calcium-dependent survival of cerebellar granule neurons.  J Biol Chem. 1999;  274 31 102-31 107
    PubMedSearch in Google Scholar
  • 42 Lin X, Bulleit R F. Cell intrinsic mechanisms regulate mouse cerebellar granule neuron differentiation.  Neurosci Lett. 1996;  220 81-84
    CrossrefPubMedSearch in Google Scholar
  • 43 Furstenberger G, Senn H J. Insulin-like growth factors and cancer.  Lancet Oncol. 2002;  3 298-302
    CrossrefPubMedSearch in Google Scholar
  • 44 Zhao M, New L, Kravchenko V V, Kato Y, Gram H, di Padova F, Olson E N, Ulevitch R J, Han J. Regulation of the MEF2 family of transcription factors by p38.  Mol Cell Biol. 1999;  19 21-30
    PubMedSearch in Google Scholar
  • 45 Kato Y, Kravchenko V V, Tapping R I, Han J, Ulevitch R J, Lee J D. BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C.  Embo J. 1997;  16 7054-7066
    CrossrefPubMedSearch in Google Scholar
  • 46 Han J, Jiang Y, Li Z, Kravchenko V V, Ulevitch R J. Activation of the transcription factor MEF2C by the MAP kinase p38 in inflammation.  Nature. 1997;  386 296-299
    CrossrefPubMedSearch in Google Scholar
  • 47 Cox D M, Du M, Marback M, Yang E C, Chan J, Siu K W, McDermott J C. Phosphorylation motifs regulating the stability and function of myocyte enhancer factor 2A.  J Biol Chem. 2003;  278 15 297-15 303
    PubMedSearch in Google Scholar
  • 48 Fujita E, Jinbo A, Matuzaki H, Konishi H, Kikkawa U, Momoi T. Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9.  Biochem Biophys Res Commun. 1999;  264 550-555
    CrossrefPubMedSearch in Google Scholar
  • 49 Okamoto S, Li Z, Ju C, Scholzke M N, Mathews E, Cui J, Salvesen G S, Bossy-Wetzel E, Lipton S A. Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis.  Proc Natl Acad Sci USA. 2002;  99 3974-3979
    CrossrefPubMedSearch in Google Scholar
  • 50 Gaudilliere B, Shi Y, Bonni A. RNA interference reveals a requirement for myocyte enhancer factor 2A in activity-dependent neuronal survival.  J Biol Chem. 2002;  277 46 442-46 446
    PubMedSearch in Google Scholar
  • 51 Linseman D A, Bartley C M, Le S S, Laessig T A, Bouchard R J, Meintzer M K, Li M, Heidenreich K A. Inactivation of the myocyte enhancer factor-2 repressor histone deacetylase-5 by endogenous Ca2+/calmodulin-dependent kinase II promotes depolarization-mediated cerebellar granule neuron survival.  J Biol Chem. 2003;  278 41 472-41 481
    PubMedSearch in Google Scholar
  • 52 Shore P, Sharrocks A D. The MADS-box family of transcription factors.  Eur J Biochem. 1995;  229 1-13
    CrossrefPubMedSearch in Google Scholar

K. A. Heidenreich, Ph. D. 

Denver VAMC-111H · 1055 Clermont Street · Denver, CO, 80220 · USA ·

Phone: +1(303)399-80203891

Fax: +1(303)393-5271

Email: kim.heidenreich@uchsc.edu