Parathyroid Hormone–Related Protein Induces Insulin Expression Through Activation of MAP Kinase–Specific Phosphatase-1 That Dephosphorylates c-Jun NH2-Terminal Kinase in Pancreatic β-Cells

  1. Bin Zhang1,
  2. Masahiro Hosaka1,
  3. Yoshie Sawada1,
  4. Seiji Torii1,
  5. Shin Mizutani1,
  6. Masato Ogata2,
  7. Tetsuro Izumi1 and
  8. Toshiyuki Takeuchi1
  1. 1Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
  2. 2Department of Biochemistry, Mie University School of Medicine, Tsu, Japan
  1. Address correspondence and reprint requests to Toshiyuki Takeuchi, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Showa-machi, Maebashi 371-8512, Japan. E-mail: tstake{at}


Parathyroid hormone–related protein (PTHrP) increases the content and mRNA level of insulin in a mouse β-cell line, MIN6, and primary-cultured mouse islets. We examined the mechanism of PTHrP-induced insulin expression. The PTHrP effect was markedly augmented by SB203580, a mitogen-activated protein (MAP) kinase inhibitor, and SB203580 itself increased insulin expression extensively, even without PTHrP. Because SB203580 inhibits both p38 and c-jun NH2-terminal kinases (JNKs), we investigated the JNK-specific inhibitor SP600125. SP600125 also increased insulin content and its mRNA level. PTHrP induced dephosphorylation of JNK1/2, and PTHrP-induced insulin expression was blocked by a dominant-negative type JNK-APF. We suspected that dual specificity MAP kinase phosphatases (MKPs) may be involved in the PTHrP-induced insulin expression by inactivating JNK1/2. MIN6 cells contained at least five MKPs, among which only MKP-1 was inducible by PTHrP. PTHrP-induced insulin expression was blocked by the MKP-1 expression inhibitor Ro-31-8220, indicating that the PTHrP effect is mediated by MKP-1. Indeed, adenoviral MKP-1 expression increased insulin expression by decreasing a phosphorylation form of JNKs and a resulting phosphorylated form of c-jun in MIN6 cells. The phosphorylated form of c-jun is known to repress cAMP-dependent insulin gene promoter activity. Thus, MKP-1 controls the insulin expression by downregulating a JNK/c-jun pathway.


    • Accepted July 30, 2003.
    • Received April 23, 2003.
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