ICA512 signaling enhances pancreatic β-cell proliferation by regulating cyclins D through STATs
| Autor: | Hassan Mziaut, Klaus-Peter Knoch, Florian Ehehalt, Katja Erdmann, Wan-Hung Fan, Mirko Trajkovski, Michele Solimena, Hendrik Bergert, Stephan Kersting, Hans-Detlev Saeger |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
STAT3 Transcription Factor
endocrine system medicine.medical_treatment Cyclin D Models Biological Cyclin D1 Insulin resistance Cyclin D2 Cyclins Insulin-Secreting Cells medicine Diabetes Mellitus STAT5 Transcription Factor Glucose homeostasis Animals Humans Insulin Regeneration Receptor-Like Protein Tyrosine Phosphatases Class 8 ddc:610 Phosphorylation Cell Proliferation Multidisciplinary biology Biological Sciences medicine.disease Cell biology Rats Insulin receptor Gene Expression Regulation biology.protein Cancer research Signal transduction Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No 2 (2008) pp. 674-679 |
| ISSN: | 0027-8424 |
| Popis: | Changes in metabolic demands dynamically regulate the total mass of adult pancreatic β-cells to adjust insulin secretion and preserve glucose homeostasis. Glucose itself is a major regulator of β-cell proliferation by inducing insulin secretion and activating β-cell insulin receptors. Here, we show that islet cell autoantigen 512 (ICA512)/IA-2, an intrinsic tyrosine phosphatase-like protein of the secretory granules, activates a complementary pathway for β-cell proliferation. On granule exocytosis, the ICA512 cytoplasmic domain is cleaved and the resulting c ytosolic fragment (ICA512-CCF) moves into the nucleus where it enhances the levels of phosphorylated STAT5 and STAT3, thereby inducing insulin gene transcription and granule biogenesis. We now show that knockdown of ICA512 decreases cyclin D1 levels and proliferation of insulinoma INS-1 cells, whereas β-cell regeneration is reduced in partially pancreatectomized ICA512 −/− mice. Conversely, overexpression of ICA512-CCF increases both cyclin D1 and D2 levels and INS-1 cell proliferation. Up-regulation of cyclin D1 and D2 by ICA512-CCF is affected by knockdown of STAT3 and STAT5, respectively, whereas it does not require insulin signaling. These results identify ICA512 as a regulator of cyclins D and β-cell proliferation through STATs and may have implication for diabetes therapy. |
| Databáze: | OpenAIRE |
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