Brought to you by Portland Press Ltd.
Published on behalf of the International Federation for Cell Biology
Cancer Cell death Cell cycle Cytoskeleton Exo/endocytosis Differentiation Division Organelles Signalling Stem cells Trafficking
Cell Biology International (1997) 21, 787–792 (Printed in Great Britain)
HISTONES AS EXTRACELLULAR MESSENGERS: EFFECTS ON GROWTH HORMONE SECRETION
O.A. BROWN, Y.E. SOSA and R.G. GOYA
aINIBIOLP—Histology and Embryology ‘B’, Faculty of Medicine, National University of La Plata, CC455, 1900, La Plata, Argentina


Abstract

Histones display hormone-like properties when present in extracellular fluids. The authors report that histones H2A and H2B possess growth hormone (GH)-releasing activityin vitroand describe the specificity and signal transduction pathways involved in these effects. Perfused and incubated rat pituitary cells were used in different sets of experiments and GH release was measured by radio-immunoassay (RIA). Perfusion of cells with 30μmhistone H2A or H2B, generated significant GH secretory responses. Cells incubated with histone H2A showed a dose- and time-dependent stimulatory effect on GH release which was blocked by peptide MB35, a synthetic fragment of histone H2A. Incubation of pituitary cells with the GH secretagogue GHRP-6, and histones revealed an additive release of GH, whereas GHRH and histones revealed a synergistic effect. The basic peptide poly-Lys did not mimetize the action of histones. Both EGTA and the protein kinase C inhibitor trifluoperazine, but not the calcium ionophre A23187, were able to reduce significantly the GH response of somatotrophs to histones. Pituitary cell incubation with 30μmforskolin alone or in the presence of H2A or H2B, stimulated GH release in the same magnitude. The results confirm previous evidence that histones may act as hypophysotropic signals and suggest, although do not prove, that this activity is receptor dependent. Calcium- and diacylglycerol-associated pathways participate in these effects.


Keywords: histones, pituitary cells, GH, MB35, calcium, diacylglycerol.


References

1 Arends, MJ, Morris, RG and Wyllie, AH (1990) Apoptosis: the role of the endonuclease. Am J Pathol 136, 593-608

2 Aten, RF and Behrman, HR (1989) A gonadotropin-releasing hormone-binding inhibitor from bovine ovaries. Purification and identification as histone H2A. J Biol Chem 264, 11,065-71

3 Atkinson, MJ, Bell, DA and Singhal, SK (1985) A naturally occurring polyclonal B cell activator of normal and autoantibody responses. J Immunol 135, 2524-33

4 Bab, I, Gazit, D, Chorev, M, Muhlrad, A, Shteyer, A, Greenberg, Z et al. (1992) Histone H4-related osteogenic growth peptide (OGP): a novel circulating stimulator of osteoblastic activity. EMBO J 11, 1867-73

5 Badamchian, M, Spangelo, BL, Damavandy, T, Macleod, RM and Goldstein, AL (1991) Complete amino acid sequence analysis of a peptide isolated from the thymus that enhances release of growth hormone and prolactin. Endocrinology 128, 1580-8

6 Badamchian, M, Wang, SS, Spangelo, BL, Damavandy, T and Goldstein, AL (1990) Chemical and biological charac-terization of MB-35: a thymic-derived peptide that stimulates the release of growth hormone and prolactin from rat anterior pituitary cells. PNEI 3, 258-65

7 Bell, DA, Morrison, B and Vandenbygaart, P (1990) Immunogenic DNA related factors: nucleosomes spontaneously released from normal murine lymphoid cells stimulate proliferation and immunoglobulin synthesis of normal mouse lymphocytes. J Clin Invest 85, 1487-96

8 Brown, OA, Sosa, YE and Goya, RG (1993) Histones and related nuclear preparations stimulate prolactin releasein vitro. Med Sci Res 21, 799-800

9 Brunk, CF, Jones, KC and James, TW (1978) Assay for nanogram quantities of DNA in cellular homogenates. Anal Biochem 92, 497-500

10 Chen, C, Wu, D and Clarke, IJ (1996) Signal transduction systems employed by synthetic GH-releasing peptides in somatotroph. J Endocrinol 148, 381-6

11 Compton, MM (1992) A biochemical hallmark of apoptosis: internucleosomal degradation of the genome. Cancer Metastasis Rev 11, 105-19

12 Frohman, LA and Jason, JO (1986) Growth hormone-releasing hormone. Endocrine Rev 7, 233-53

13 Goya, RG, Castro, MG, Linton, EA, Sosa, YE and Lowry, PJ (1993) Histones and related preparations interfere with immunoassays for peptide hormones. Peptides 14(4), 777-81

14 Goya, RG, Castro, MG, Saphier, PW, Sosa, YE and Lowry, PJ (1993) Thymus-pituitary interactions during ageing. Age & Ageing 22, S19-25

15 Goya, RG, Quigley, KL, Takahashi, S, Reichhart, R and Meites, J (1989) Differential effect of homeostatic thymus hormone on plasma thyrotropin and growth hormone in young and old rats. Mech Age Devel 49, 119-28

16 Goya, RG, Sosa, YE, Brown, OA and Dardenne, M (1994) In vitro. Ann NY Acad Sci 741, 108-14

17 Goya, RG, Sosa, YE, Quigley, KL, Reichhart, R and Meites, J (1990) Homeostatic thymus hormone stimulates cortico-sterone secretion in a dose- and age-dependent manner in rats. Neuroendocrinology 51, 59-63

18 Hefeneider, SH, Cornell, KA, Brown, LE, Bakke, AC, McCoy, SL and Bennet, RM (1992) Nucleosomes and DNA bind to specific cell-surface molecule on murine cells and induce cytokine production. Clin Immunol Immunopathol 63, 245-9

19 Jacob, L, Viard, JP, Allenet, B, Anin, MF, Slama, FB, Vandekerckhove, J et al. (1989) A monoclonal anti-double-stranded DNA autoantibody binds to a 94-kDa cell-surface protein on various cell types via nucleosomes or a DNA-histone complex. Proc Natl Acad Sci USA 86, 4669-73

20 Le Lann, AD, Fournie, GJ, Boissier, L, Toutain, PL and Benoist, H (1994) In Vitro. Cancer Immunol Immunother 39, 185-92

21 McCroskey, MC, Palazuk, BJ, Pierce-Ramsey, PA, Colca, JR and Pearson, JD (1989) Insulin-like effects of histones H3 and H4 on isolated rat adipocytes. Biochim Biophys Acta 1011, 212-9

22 Raptis, L and Menard, HA (1980) Quantitation and characteriz-ation of plasma DNA in normals and patients with systemic lupus erythematosus. J Clin Invest 66, 1391-9

23 Reichhart, R, Zeppezauer, M and Jörnvall, H (1985) Prep-arations of homeostatic thymus hormone consist predominantly of histones 2A and 2B and suggest additional histone functions. Proc Natl Acad Sci USA 82, 4871-5

24 Steinman, CR (1975) Free DNA in serum and plasma from normal adults. J Clin Invest 56, 512-5

25 Waga, S, Tan, EM and Rubin, RL (1987) Identification and iso-lation of soluble histones from bovine milk and serum. Biochem J 244, 675-82

26 Weiss, J and Jameson, JL (1993) Perifused pituitary cells as a model for studies of gonadotropin biosynthesis and secretion. Trends Endocrinol Metab 4, 265-70

27 Yasutomo, Y, Suga, T, Wada, S, Kosano, H, Takishima, K, Mamiya, G et al. (1991) Purification and partial sequencing of inhibitory factor on renal membrane adenylate cyclase in pancreatic cancer extract: identity with histones H1b or H1d. Biochem Biophys Res Commun 176, 255-61


doi:10.1006/cbir.1998.0203


ISSN Print: 1065-6995
ISSN Electronic: 1095-8355
Published by Portland Press Limited on behalf of the International Federation for Cell Biology (IFCB)