A mutant receptor with enhanced dominant-negative activity for the blockade of human prolactin signalling

J Mol Endocrinol. 2004 Apr;32(2):385-96. doi: 10.1677/jme.0.0320385.

Abstract

An effective mechanism for interfering with prolactin signalling would provide a powerful tool for clarifying the importance of prolactin in breast cancer, as well as for investigating functions of prolactin in other tissues. Based on our previous identification of a dominant-negative mutation in the growth hormone receptor that causes familial short stature, we investigated the potential for using a similar truncated mutant of the prolactin receptor (PRLR1-242). Like the mutant growth hormone receptor, PRLR1-242 exerts an exceptionally powerful dominant-negative effect. A probable explanation for the strong dominant-negative activity of this class of mutation is that, lacking internalisation motifs, the truncated mutants accumulate at the cell surface and form non-functional heterodimers with wild-type receptors. In accordance with evidence for heterodimer formation between the two receptors, PRLR1-242 also blocks signalling by the growth hormone receptor. When expressed from an adenoviral vector, PRLR1-242 inhibits activation of STAT5 (signal transducer and activator of transcription 5) by prolactin in T47-D breast cancer cells, and blocks the ability of prolactin to induce proliferation in these cells. Thus PRLR1-242 provides an effective means of blocking the responsiveness of target tissues to human prolactin.

MeSH terms

  • Adenoviridae / genetics
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Cell Proliferation / drug effects
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Genes, Dominant
  • Humans
  • Milk Proteins / metabolism
  • Mutation*
  • Prolactin / genetics
  • Prolactin / metabolism*
  • Prolactin / pharmacology
  • Receptors, Prolactin / drug effects
  • Receptors, Prolactin / genetics*
  • Receptors, Prolactin / metabolism
  • STAT5 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Milk Proteins
  • Receptors, Prolactin
  • STAT5 Transcription Factor
  • Trans-Activators
  • Prolactin