Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1994 Dec 20;91(26):12599–12603. doi: 10.1073/pnas.91.26.12599

Regulation of neuronal Bcl2 protein expression and calcium homeostasis by transforming growth factor type beta confers wide-ranging protection on rat hippocampal neurons.

J H Prehn 1, V P Bindokas 1, C J Marcuccilli 1, S Krajewski 1, J C Reed 1, R J Miller 1
PMCID: PMC45486  PMID: 7809085

Abstract

Excessive activation of glutamate receptors accompanied by Ca2+ overloading is thought to be responsible for the death of neurons in various conditions including stroke and epilepsy. Neurons also die if deprived of important growth factors and trophic influences, conditions sensitive to certain oncogene products such as the Bcl2 protein. We now demonstrate that transforming growth factor type beta (TGF-beta) prevents neuronal Ca2+ overloading of rat hippocampal neurons in response to the glutamatergic agonist N-methyl-D-aspartate or the Ca2+ ionophore 4-Br-A23187 and, in addition, leads to a substantial increase in neuronal Bcl2 protein expression. Parallel cytotoxicity experiments demonstrate that treatment with TGF-beta protects rat hippocampal neurons from death induced by excitotoxicity, trophic factor removal, and oxidative injury. Thus, TGF-beta may protect against a wide range of toxic insults by regulating two factors with great importance for neuronal viability.

Full text

PDF
12599

Images in this article

12600Fig. 1
on p.12600
12601Fig. 2
on p.12601
12602Fig. 6
on p.12602

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abele A. E., Scholz K. P., Scholz W. K., Miller R. J. Excitotoxicity induced by enhanced excitatory neurotransmission in cultured hippocampal pyramidal neurons. Neuron. 1990 Mar;4(3):413–419. doi: 10.1016/0896-6273(90)90053-i. [DOI] [PubMed] [Google Scholar]
  2. Bindokas V. P., Brorson J. R., Miller R. J. Characteristics of voltage sensitive calcium channels in dendrites of cultured rat cerebellar neurons. Neuropharmacology. 1993 Nov;32(11):1213–1220. doi: 10.1016/0028-3908(93)90015-u. [DOI] [PubMed] [Google Scholar]
  3. Choi D. W. Excitotoxic cell death. J Neurobiol. 1992 Nov;23(9):1261–1276. doi: 10.1002/neu.480230915. [DOI] [PubMed] [Google Scholar]
  4. Duchen M. R. Ca(2+)-dependent changes in the mitochondrial energetics in single dissociated mouse sensory neurons. Biochem J. 1992 Apr 1;283(Pt 1):41–50. doi: 10.1042/bj2830041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Garcia I., Martinou I., Tsujimoto Y., Martinou J. C. Prevention of programmed cell death of sympathetic neurons by the bcl-2 proto-oncogene. Science. 1992 Oct 9;258(5080):302–304. doi: 10.1126/science.1411528. [DOI] [PubMed] [Google Scholar]
  6. Hartley D. M., Kurth M. C., Bjerkness L., Weiss J. H., Choi D. W. Glutamate receptor-induced 45Ca2+ accumulation in cortical cell culture correlates with subsequent neuronal degeneration. J Neurosci. 1993 May;13(5):1993–2000. doi: 10.1523/JNEUROSCI.13-05-01993.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Heine U. I., Burmester J. K., Flanders K. C., Danielpour D., Munoz E. F., Roberts A. B., Sporn M. B. Localization of transforming growth factor-beta 1 in mitochondria of murine heart and liver. Cell Regul. 1991 Jun;2(6):467–477. doi: 10.1091/mbc.2.6.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hockenbery D. M., Oltvai Z. N., Yin X. M., Milliman C. L., Korsmeyer S. J. Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell. 1993 Oct 22;75(2):241–251. doi: 10.1016/0092-8674(93)80066-n. [DOI] [PubMed] [Google Scholar]
  9. Hockenbery D., Nuñez G., Milliman C., Schreiber R. D., Korsmeyer S. J. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990 Nov 22;348(6299):334–336. doi: 10.1038/348334a0. [DOI] [PubMed] [Google Scholar]
  10. Héron A., Pollard H., Dessi F., Moreau J., Lasbennes F., Ben-Ari Y., Charriaut-Marlangue C. Regional variability in DNA fragmentation after global ischemia evidenced by combined histological and gel electrophoresis observations in the rat brain. J Neurochem. 1993 Nov;61(5):1973–1976. doi: 10.1111/j.1471-4159.1993.tb09843.x. [DOI] [PubMed] [Google Scholar]
  11. Kane D. J., Sarafian T. A., Anton R., Hahn H., Gralla E. B., Valentine J. S., Ord T., Bredesen D. E. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species. Science. 1993 Nov 19;262(5137):1274–1277. doi: 10.1126/science.8235659. [DOI] [PubMed] [Google Scholar]
  12. Krajewski S., Tanaka S., Takayama S., Schibler M. J., Fenton W., Reed J. C. Investigation of the subcellular distribution of the bcl-2 oncoprotein: residence in the nuclear envelope, endoplasmic reticulum, and outer mitochondrial membranes. Cancer Res. 1993 Oct 1;53(19):4701–4714. [PubMed] [Google Scholar]
  13. Logan A., Berry M. Transforming growth factor-beta 1 and basic fibroblast growth factor in the injured CNS. Trends Pharmacol Sci. 1993 Sep;14(9):337–342. doi: 10.1016/0165-6147(93)90007-7. [DOI] [PubMed] [Google Scholar]
  14. Loo D. T., Copani A., Pike C. J., Whittemore E. R., Walencewicz A. J., Cotman C. W. Apoptosis is induced by beta-amyloid in cultured central nervous system neurons. Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7951–7955. doi: 10.1073/pnas.90.17.7951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Minta A., Tsien R. Y. Fluorescent indicators for cytosolic sodium. J Biol Chem. 1989 Nov 15;264(32):19449–19457. [PubMed] [Google Scholar]
  16. Negrini M., Silini E., Kozak C., Tsujimoto Y., Croce C. M. Molecular analysis of mbcl-2: structure and expression of the murine gene homologous to the human gene involved in follicular lymphoma. Cell. 1987 May 22;49(4):455–463. doi: 10.1016/0092-8674(87)90448-x. [DOI] [PubMed] [Google Scholar]
  17. Negulescu P. A., Harootunian A., Tsien R. Y., Machen T. E. Fluorescence measurements of cytosolic free Na concentration, influx and efflux in gastric cells. Cell Regul. 1990 Feb;1(3):259–268. doi: 10.1091/mbc.1.3.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nicholls D., Akerman K. Mitochondrial calcium transport. Biochim Biophys Acta. 1982 Sep 1;683(1):57–88. doi: 10.1016/0304-4173(82)90013-1. [DOI] [PubMed] [Google Scholar]
  19. Prehn J. H., Backhauss C., Krieglstein J. Transforming growth factor-beta 1 prevents glutamate neurotoxicity in rat neocortical cultures and protects mouse neocortex from ischemic injury in vivo. J Cereb Blood Flow Metab. 1993 May;13(3):521–525. doi: 10.1038/jcbfm.1993.67. [DOI] [PubMed] [Google Scholar]
  20. Raff M. C., Barres B. A., Burne J. F., Coles H. S., Ishizaki Y., Jacobson M. D. Programmed cell death and the control of cell survival: lessons from the nervous system. Science. 1993 Oct 29;262(5134):695–700. doi: 10.1126/science.8235590. [DOI] [PubMed] [Google Scholar]
  21. Ratan R. R., Murphy T. H., Baraban J. M. Oxidative stress induces apoptosis in embryonic cortical neurons. J Neurochem. 1994 Jan;62(1):376–379. doi: 10.1046/j.1471-4159.1994.62010376.x. [DOI] [PubMed] [Google Scholar]
  22. Reed J. C. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994 Jan;124(1-2):1–6. doi: 10.1083/jcb.124.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Unsicker K., Flanders K. C., Cissel D. S., Lafyatis R., Sporn M. B. Transforming growth factor beta isoforms in the adult rat central and peripheral nervous system. Neuroscience. 1991;44(3):613–625. doi: 10.1016/0306-4522(91)90082-y. [DOI] [PubMed] [Google Scholar]
  24. Wyllie A. H., Kerr J. F., Currie A. R. Cell death: the significance of apoptosis. Int Rev Cytol. 1980;68:251–306. doi: 10.1016/s0074-7696(08)62312-8. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES