A mutant receptor with enhanced dominant-negative activity for the blockade of human prolactin signalling.
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.
Flynn
A
A
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, UK.
Whittington
H
H
Goffin
V
V
Uney
J
J
Norman
M
M
D000256:Adenoviridae / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D019281:Dimerization; D005799:Genes, Dominant; D006801:Humans; D008894:Milk Proteins / Q000378:metabolism; D009154:Mutation; D011388:Prolactin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011981:Receptors, Prolactin / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011981:Receptors, Prolactin; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D011388:Prolactin