The hepatocyte is a direct target for transforming-growth factor beta activation via the insulin-like growth factor II/mannose 6-phosphate receptor.
OBJECTIVE
The cation-independent mannose 6-phosphate receptor (CIMPR) is overexpressed in hepatocytes during liver regeneration and has been implicated in the maturation of latent pro-transforming growth factor beta (TGFbeta). In this study, we have: (1) kinetically characterized the changes in CIMPR expression in regenerating liver and cultured proliferating hepatocytes; and (2) assessed the contribution of hepatocyte via the CIMPR to latent pro-TGFbeta activation.


METHODS
The expression of CIMPR protein and mRNA in livers collected after partial hepatectomy and hepatocyte primary cultures was analyzed by Western and Northern blotting. Activity of latent pro-TGFbeta was assessed by inhibition of [3H] methylthymidine incorporation into DNA.


RESULTS
The expression of the CIMPR protein and/or mRNA progressively increased after 8 h in regenerating liver and 42-46 h in cultured hepatocytes, prior to the onset of DNA replication. Both mature TGFbeta and latent pro-TGFbeta inhibited epidermal growth factor-stimulated DNA synthesis in hepatocytes in a dose-dependent manner. The effect of latent pro-TGFbeta was reversed by two ligands of the CIMPR: beta-galactosidase, a mannose 6-phosphate containing protein, and a CIMPR antibody.


CONCLUSIONS
(1) The induction of the CIMPR gene during liver regeneration and hepatocyte culture occurs in mid G1 phase; and (2) the CIMPR mediates latent proTGFbeta activation and thus may act, by targeting TGFbeta to hepatocytes, as a negative regulator of hepatocyte growth.
Villevalois-Cam
Laurence
L
INSERM U522, Unité de Recherches Hépatologiques, IFR 97, Hôpital Pontchaillou, 35033 Rennes, France.
Rescan
Claude
C
Gilot
David
D
Ezan
Frédéric
F
Loyer
Pascal
P
Desbuquois
Bernard
B
Guguen-Guillouzo
Christiane
C
Baffet
Georges
G
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D008024:Ligands; D008115:Liver Regeneration / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017527:Receptor, IGF Type 2 / Q000235:genetics* / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1
D008024:Ligands; D010446:Peptide Fragments; D011498:Protein Precursors; D017527:Receptor, IGF Type 2; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1