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Scg5  -  secretogranin V

Mus musculus

Synonyms: 7B2, AI325031, Neuroendocrine protein 7B2, Secretogranin V, Secretogranin-5, ...
 
 
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Disease relevance of Scg5

  • 7B2 null mice have no demonstrable PC2 activity, are deficient in processing islet hormones, and display hypoglycemia, hyperproinsulinemia, and hypoglucagonemia [1].
  • A hypoglycemic crisis coupled with respiratory distress and intensive internal thrombosis most likely results in rapid deterioration and death of the 7B2 null [2].
  • Interestingly, adrenalectomized 7B2 nulls also developed unexpectedly severe obesity [3].
  • In this study, we determined that 7B2 can be phosphorylated in Rin cells (a rat insulinoma cell line) and cultured chromaffin cells, but not in AtT-20 cells (derived from mouse anterior pituitary) [4].
  • Convertase PC2 and the neuroendocrine polypeptide 7B2 are co-induced and processed during neuronal differentiation of P19 embryonal carcinoma cells [5].
 

High impact information on Scg5

  • Elevated corticosterone, therefore, seems to play a central role in the lethal phenotype of the 7B2 null, whereas a 7B2-mediated dopaminergic deficiency state may be involved in the actual ACTH hypersecretion phenomenon [3].
  • Because hypothalamic inhibitory dopaminergic control represents the major influence on intermediate lobe proopiomelanocortin-derived peptide secretion, dopamine levels were measured, and they revealed that 7B2 null pituitaries contained only one-fourth of WT pituitary dopamine [3].
  • Differential expression of 7B2 may contribute to the difference between B6 and C3H mice not only in glucagon production and secretion but also in glucose tolerance [6].
  • Differences of pancreatic expression of 7B2 between C57BL/6J and C3H/HeJ mice and genetic polymorphisms at its locus (Sgne1) [6].
  • Sequencing of the 7B2 gene promoter and cDNA in the two strains revealed seven single nucleotide polymorphisms and one dinucleotide insertion/deletion in the cDNA as well as a single nucleotide polymorphism and two insertions/deletions in the promoter [6].
 

Chemical compound and disease context of Scg5

 

Biological context of Scg5

  • To test this hypothesis, we created a null mutation in 7B2 employing a novel transposon-facilitated technique and compared the phenotypes of 7B2 and PC2 nulls [1].
  • To verify this possibility, we introduced into mouse corticotroph AtT20 cells a retroviral vector carrying either a sense or an antisense 7B2 transgene to induce higher and lower 7B2 expression, respectively [8].
  • Neuroendocrine protein 7B2 can be inactivated by phosphorylation within the secretory pathway [4].
  • Taken together, our results show that residues 242-248 do not play a significant role in defining the substrate specificity of PC2 but do contribute greatly to binding 7B2 and are critical for inhibition with the 7B2 CT peptide [9].
  • Mutations in the catalytic domain of prohormone convertase 2 result in decreased binding to 7B2 and loss of inhibition with 7B2 C-terminal peptide [9].
 

Anatomical context of Scg5

  • Electron microscopy of neurointermediate lobe melanotrophs reveals the presence of a significantly greater number of secretory granules in both 7B2 and PC2 nulls compared with wild-type controls [10].
  • Analysis of CCK content in extracts of whole forebrain from PC2 and 7B2 null mouse brain showed a significant decrease relative to wild-type brains [11].
  • Recombinant proPC2 purified from the medium of CHO cells overexpressing both the prohormone convertase (PC) precursor proPC2 and the 21-kDa amino terminal portion of the neuroendocrine protein 7B2 can spontaneously convert to an active species [12].
  • Immunoreactivity for 7B2 was present in rat, mouse, and human gonadotropes, in intermediate lobe cells and posterior lobe nerve fibers in rats and mice, in rat hypothalamus (particularly in the median eminence), and in eight human pituitary gonadotropinomas [7].
  • In an immunohistochemical study, MON-100 exhibited strong reactivity with the intermediate lobe of the Xenopus pituitary gland, a tissue previously shown to contain 7B2 mRNA [13].
 

Associations of Scg5 with chemical compounds

  • When 7B2 nulls were transferred onto the B6 background, they survived and showed greatly decreased circulating corticosterone and increased blood glucose levels, most likely due to the comparatively higher adrenal resistance of the B6 strain to ACTH stimulation [14].
  • Phosphoamino acid analysis of Rin cell 7B2 indicated the presence of phosphorylated serine and threonine [4].
  • The neuroendocrine convertase PC2 and 7B2, its specific binding protein, are co-induced during neuronal differentiation of P19 cells with retinoic acid, whereas the other convertases are not or follow different patterns of temporal expression [5].
  • Our findings suggest that 7B2, neuromedin B, and neuromedin U may be involved in pituitary function [7].
  • Pituitary, hypothalamic and pancreatic 7B2 concentrations in rats with streptozotocin-induced diabetes and spontaneously diabetic mice [15].
 

Physical interactions of Scg5

  • We previously showed that the neuroendocrine polypeptide 7B2 transiently interacts with prohormone convertase PC2 in the secretory pathway of neuroendocrine cells [16].
  • The expression of convertase PC2 and its specific binding peptide 7B2 are co-induced during neuronal differentiation of P19 cells [17].
 

Regulatory relationships of Scg5

  • Here we demonstrate that the processed, but not the intact, form of 7B2 can enhance the in vitro cleavage of newly synthesized prohormone proopiomelanocortin (POMC) in lysates of Xenopus intermediate pituitary cells [16].
  • The neuroendocrine protein 7B2 and its 31-residue carboxyl-terminal (CT) peptide potently and specifically inhibit prohormone convertase 2 (PC2) [18].
 

Other interactions of Scg5

  • The prohormone convertase PC2 requires the aid of a helper protein, known as 7B2, for production of active enzyme [19].
  • ACTH secretion by mouse corticotroph AtT20 cells is negatively modulated by the intracellular level of 7B2 [8].
  • The maturation of PC2 requires the aid of a helper protein, 7B2, in order for the zymogen to become an active enzyme species [10].
  • In contrast with the cerebral changes, PC2 deficiency was without effect on proCCK synthesis and processing in intestinal endocrine cells, whereas 7B2 deficiency halved the concentration of bioactive CCK in the intestine [20].
  • Similar inhibitory effects were noted on the processing of proPC3, proinsulin, and 7B2 [21].
 

Analytical, diagnostic and therapeutic context of Scg5

  • Because proprotein convertase (PC)2 and its 7B2 helper protein are required for this processing, we quantified islet mRNA levels by RT-PCR and protein levels by immunoblotting [6].
  • Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion [3].
  • This was determined by in situ hybridization, using a mouse 7B2 cDNA and an intronic fragment of the corresponding human gene as probes [22].
  • The convertases levels were quantified by Western blot, as well as the protein 7B2 which is required for the production of active PC2 [23].
  • Using MON-100, immunoprecipitation analysis of newly synthesized proteins produced by in vitro incubated Xenopus neurointermediate lobes revealed the biosynthesis of a single protein of Mr 24 kDa, the expected size of the 7B2 protein [13].

References

  1. The neuroendocrine protein 7B2 is required for peptide hormone processing in vivo and provides a novel mechanism for pituitary Cushing's disease. Westphal, C.H., Muller, L., Zhou, A., Zhu, X., Bonner-Weir, S., Schambelan, M., Steiner, D.F., Lindberg, I., Leder, P. Cell (1999) [Pubmed]
  2. The lethal form of Cushing's in 7B2 null mice is caused by multiple metabolic and hormonal abnormalities. Sarac, M.S., Zieske, A.W., Lindberg, I. Endocrinology (2002) [Pubmed]
  3. Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion. Laurent, V., Kimble, A., Peng, B., Zhu, P., Pintar, J.E., Steiner, D.F., Lindberg, I. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  4. Neuroendocrine protein 7B2 can be inactivated by phosphorylation within the secretory pathway. Lee, S.N., Hwang, J.R., Lindberg, I. J. Biol. Chem. (2006) [Pubmed]
  5. Convertase PC2 and the neuroendocrine polypeptide 7B2 are co-induced and processed during neuronal differentiation of P19 embryonal carcinoma cells. Jeannotte, R., Paquin, J., Petit-Turcotte, C., Day, R. DNA Cell Biol. (1997) [Pubmed]
  6. Differences of pancreatic expression of 7B2 between C57BL/6J and C3H/HeJ mice and genetic polymorphisms at its locus (Sgne1). Schmidt, G., Sirois, F., Anini, Y., Kauri, L.M., Gyamera-Acheampong, C., Fleck, E., Scott, F.W., Chrétien, M., Mbikay, M. Diabetes (2006) [Pubmed]
  7. Localization of 7B2, neuromedin B, and neuromedin U in specific cell types of rat, mouse, and human pituitary, in rat hypothalamus, and in 30 human pituitary and extrapituitary tumors. Steel, J.H., Van Noorden, S., Ballesta, J., Gibson, S.J., Ghatei, M.A., Burrin, J., Leonhardt, U., Domin, J., Bloom, S.R., Polak, J.M. Endocrinology (1988) [Pubmed]
  8. ACTH secretion by mouse corticotroph AtT20 cells is negatively modulated by the intracellular level of 7B2. Bergeron, F., Sirois, F., Mbikay, M. FEBS Lett. (2002) [Pubmed]
  9. Mutations in the catalytic domain of prohormone convertase 2 result in decreased binding to 7B2 and loss of inhibition with 7B2 C-terminal peptide. Apletalina, E.V., Muller, L., Lindberg, I. J. Biol. Chem. (2000) [Pubmed]
  10. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Laurent, V., Jaubert-Miazza, L., Desjardins, R., Day, R., Lindberg, I. Endocrinology (2004) [Pubmed]
  11. PC2 and 7B2 null mice demonstrate that PC2 is essential for normal pro-CCK processing. Vishnuvardhan, D., Connolly, K., Cain, B., Beinfeld, M.C. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  12. The proteolytic maturation of prohormone convertase 2 (PC2) is a pH-driven process. Lamango, N.S., Apletalina, E., Liu, J., Lindberg, I. Arch. Biochem. Biophys. (1999) [Pubmed]
  13. Development of a monoclonal antibody against recombinant neuroendocrine 7B2 protein. van Duijnhoven, H.L., Ayoubi, T.A., Timmer, E.D., Braks, A.A., Roebroek, A.J., Martens, G.J., van de Ven, W.J. FEBS Lett. (1989) [Pubmed]
  14. Strain-dependent influences on the hypothalamo-pituitary-adrenal axis profoundly affect the 7B2 and PC2 null phenotypes. Peinado, J.R., Laurent, V., Lee, S.N., Peng, B.W., Pintar, J.E., Steiner, D.F., Lindberg, I. Endocrinology (2005) [Pubmed]
  15. Pituitary, hypothalamic and pancreatic 7B2 concentrations in rats with streptozotocin-induced diabetes and spontaneously diabetic mice. Suzuki, H., Suzuki, Y., Ohtake, R., Kobori, H., Hashigami, Y., Shimoda, S.I. Pancreas (1988) [Pubmed]
  16. The neuroendocrine chaperone 7B2 can enhance in vitro POMC cleavage by prohormone convertase PC2. Braks, J.A., Martens, G.J. FEBS Lett. (1995) [Pubmed]
  17. Coordinate regulation of neuroendocrine convertase PC2 and peptide 7B2 in P19 neurons. Petit-Turcotte, C., Paquin, J. Peptides (2000) [Pubmed]
  18. Structure-function analysis of the 7B2 CT peptide. Apletalina, E.V., Juliano, M.A., Juliano, L., Lindberg, I. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  19. Intrapituitary adenoviral administration of 7B2 can extend life span and reverse endocrinological deficiencies in 7B2 null mice. Sarac, M.S., Windeatt, S., Castro, M.G., Lindberg, I. Endocrinology (2002) [Pubmed]
  20. Increased synthesis but decreased processing of neuronal proCCK in prohormone convertase 2 and 7B2 knockout animals. Rehfeld, J.F., Lindberg, I., Friis-Hansen, L. J. Neurochem. (2002) [Pubmed]
  21. Long-term elevation of free fatty acids leads to delayed processing of proinsulin and prohormone convertases 2 and 3 in the pancreatic beta-cell line MIN6. Furukawa, H., Carroll, R.J., Swift, H.H., Steiner, D.F. Diabetes (1999) [Pubmed]
  22. Assignment of the gene for neuroendocrine protein 7B2 (SGNE1 locus) to mouse chromosome region 2[E3-F3] and to human chromosome region 15q11-q15. Mattei, M.G., Mbikay, M., Sylla, B.S., Lenoir, G., Mattei, J.F., Seidah, N.G., Chretien, M. Genomics (1990) [Pubmed]
  23. The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease. Winsky-Sommerer, R., Grouselle, D., Rougeot, C., Laurent, V., David, J.P., Delacourte, A., Dournaud, P., Seidah, N.G., Lindberg, I., Trottier, S., Epelbaum, J. Neuroscience (2003) [Pubmed]
 
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