Streptozotocin, an analog of N-acetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins

M. D. Roos, W. Xie, Kaihong Su, J. A. Clark, X. Yang, E. Chin, A. J. Paterson, J. E. Kudlow

Research output: Contribution to journalArticle

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Abstract

Streptozotocin (STZ), an analog of N-acetylglucosamine (GlcNAc), is a specific toxin for the pancreatic β cell. We found that treatment of rats with STZ results in an early β-cell-specific increase in the level of intracellular protein modification by O-linked GlcNAc (O-GlcNAc). Using a model O-GlcNAc peptide based on the transcription factor Sp1, we show that treatment of cultured cells with STZ during peptide biosynthesis results in hyperglycosylation of the peptide as a result of the ability of STZ to specifically inhibit the activity of O-GlcNAc-selective N-acetyl-β-D- glucosaminidase. Although this inhibitory activity of STZ probably can occur in all cells, we found, using in situ hybridization, that β cells express very high levels of the mRNA encoding the enzyme responsible for cytoplasmic protein O-glycosylation, O-GlcNAc transferase (OGT). These findings suggest that the pancreatic β cell is particularly sensitive to the toxicity of STZ because it expresses such high levels of OGT. When STZ blocks O-GlcNAc removal from intracellular proteins, the cell with the most rapid on-rate for O-GlcNAc, the β cell, will experience the most rapid accumulation of this protein modification. Because we also show that the on-rate of O-GlcNAc is substrate driven in several cell types, we speculate that the β cell, with its high level of OGT, may also respond to elevations of blood sugar with increased protein modification by O-GlcNAc. Thus, this proposed mechanism of STZ toxicity on the β cell may result from an exaggeration of a heretofore unrecognized physiological response to glucose mediated through the high level of OGT in these cells.

Original languageEnglish (US)
Pages (from-to)422-432
Number of pages11
JournalProceedings of the Association of American Physicians
Volume110
Issue number5
StatePublished - Sep 23 1998

Fingerprint

Acetylglucosamine
Streptozocin
Proteins
Peptide Biosynthesis
Sp1 Transcription Factor
Hexosaminidases
Peptides
Glycosylation
In Situ Hybridization
Blood Glucose
Cultured Cells
Glucose

Keywords

  • Diabetes
  • Gene transcriptions
  • Glucotoxicity
  • Glycosylation
  • β cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Streptozotocin, an analog of N-acetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins. / Roos, M. D.; Xie, W.; Su, Kaihong; Clark, J. A.; Yang, X.; Chin, E.; Paterson, A. J.; Kudlow, J. E.

In: Proceedings of the Association of American Physicians, Vol. 110, No. 5, 23.09.1998, p. 422-432.

Research output: Contribution to journalArticle

Roos, MD, Xie, W, Su, K, Clark, JA, Yang, X, Chin, E, Paterson, AJ & Kudlow, JE 1998, 'Streptozotocin, an analog of N-acetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins', Proceedings of the Association of American Physicians, vol. 110, no. 5, pp. 422-432.
Roos, M. D. ; Xie, W. ; Su, Kaihong ; Clark, J. A. ; Yang, X. ; Chin, E. ; Paterson, A. J. ; Kudlow, J. E. / Streptozotocin, an analog of N-acetylglucosamine, blocks the removal of O-GlcNAc from intracellular proteins. In: Proceedings of the Association of American Physicians. 1998 ; Vol. 110, No. 5. pp. 422-432.
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AU - Roos, M. D.

AU - Xie, W.

AU - Su, Kaihong

AU - Clark, J. A.

AU - Yang, X.

AU - Chin, E.

AU - Paterson, A. J.

AU - Kudlow, J. E.

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N2 - Streptozotocin (STZ), an analog of N-acetylglucosamine (GlcNAc), is a specific toxin for the pancreatic β cell. We found that treatment of rats with STZ results in an early β-cell-specific increase in the level of intracellular protein modification by O-linked GlcNAc (O-GlcNAc). Using a model O-GlcNAc peptide based on the transcription factor Sp1, we show that treatment of cultured cells with STZ during peptide biosynthesis results in hyperglycosylation of the peptide as a result of the ability of STZ to specifically inhibit the activity of O-GlcNAc-selective N-acetyl-β-D- glucosaminidase. Although this inhibitory activity of STZ probably can occur in all cells, we found, using in situ hybridization, that β cells express very high levels of the mRNA encoding the enzyme responsible for cytoplasmic protein O-glycosylation, O-GlcNAc transferase (OGT). These findings suggest that the pancreatic β cell is particularly sensitive to the toxicity of STZ because it expresses such high levels of OGT. When STZ blocks O-GlcNAc removal from intracellular proteins, the cell with the most rapid on-rate for O-GlcNAc, the β cell, will experience the most rapid accumulation of this protein modification. Because we also show that the on-rate of O-GlcNAc is substrate driven in several cell types, we speculate that the β cell, with its high level of OGT, may also respond to elevations of blood sugar with increased protein modification by O-GlcNAc. Thus, this proposed mechanism of STZ toxicity on the β cell may result from an exaggeration of a heretofore unrecognized physiological response to glucose mediated through the high level of OGT in these cells.

AB - Streptozotocin (STZ), an analog of N-acetylglucosamine (GlcNAc), is a specific toxin for the pancreatic β cell. We found that treatment of rats with STZ results in an early β-cell-specific increase in the level of intracellular protein modification by O-linked GlcNAc (O-GlcNAc). Using a model O-GlcNAc peptide based on the transcription factor Sp1, we show that treatment of cultured cells with STZ during peptide biosynthesis results in hyperglycosylation of the peptide as a result of the ability of STZ to specifically inhibit the activity of O-GlcNAc-selective N-acetyl-β-D- glucosaminidase. Although this inhibitory activity of STZ probably can occur in all cells, we found, using in situ hybridization, that β cells express very high levels of the mRNA encoding the enzyme responsible for cytoplasmic protein O-glycosylation, O-GlcNAc transferase (OGT). These findings suggest that the pancreatic β cell is particularly sensitive to the toxicity of STZ because it expresses such high levels of OGT. When STZ blocks O-GlcNAc removal from intracellular proteins, the cell with the most rapid on-rate for O-GlcNAc, the β cell, will experience the most rapid accumulation of this protein modification. Because we also show that the on-rate of O-GlcNAc is substrate driven in several cell types, we speculate that the β cell, with its high level of OGT, may also respond to elevations of blood sugar with increased protein modification by O-GlcNAc. Thus, this proposed mechanism of STZ toxicity on the β cell may result from an exaggeration of a heretofore unrecognized physiological response to glucose mediated through the high level of OGT in these cells.

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