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Transactivation of the TPA-responsive element by the oncogenic C-erbB-2 protein is partly mediated by protein kinase

A Fujimoto1, S Kai, T Akiyama

  • 1Department of Oncology, University of Tokyo, Japan.

Biochemical and Biophysical Research Communications
|July 31, 1991
PubMed

Insights

A mutant c-erbB-2 gene transforms cells by enhancing tyrosine kinase activity. This active protein partly signals through protein kinase C, leading to transcriptional activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The c-erbB-2 gene, when mutated, can lead to cellular transformation.
  • Overexpression of wild-type c-erbB-2 does not typically cause transformation.
  • The transmembrane domain mutation in c-erbB-2 is crucial for its oncogenic potential.

Purpose of the Study:

  • To investigate the transforming ability of a specific mutant c-erbB-2.
  • To elucidate the downstream signaling pathways activated by the mutant c-erbB-2.
  • To determine the role of protein kinase C in the oncogenic signaling of mutant c-erbB-2.

Main Methods:

  • Generating and expressing mutant and wild-type c-erbB-2 in NIH3T3 cells.
  • Assessing tyrosine kinase activity in vitro.
  • Measuring the stimulation of response elements (TPA, serum, cAMP) via transient and stable expression.
  • Utilizing protein kinase C down-regulation and inhibition (H7) to study pathway involvement.

Main Results:

  • The mutant c-erbB-2, with Glu at position 659, transformed NIH3T3 cells, unlike wild-type c-erbB-2.
  • Mutant c-erbB-2 exhibited enhanced in vitro tyrosine kinase activity.
  • Active c-erbB-2 significantly stimulated the TPA response element, and to lesser extents, serum and cAMP response elements.
  • Wild-type c-erbB-2 did not stimulate these elements.
  • Protein kinase C inhibition partially blocked the transactivation of the TPA response element by active c-erbB-2.

Conclusions:

  • The mutant c-erbB-2 protein possesses oncogenic potential due to enhanced tyrosine kinase activity.
  • Protein kinase C plays a partial role in the oncogenic signaling cascade initiated by active c-erbB-2.
  • Active c-erbB-2 promotes Jun/Fos-mediated transcriptional activation through pathways involving protein kinase C.

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