HIP/PAP stimulates liver regeneration after partial hepatectomy and combines mitogenic and anti-apoptotic functions through the PKA signaling pathway.
The HIP/PAP (=human Reg-2) C-type lectin encoding gene is activated in primary liver cancers. In normal liver, the protein is undetectable in normal mature hepatocytes and found only in some ductular cells, representing potential hepatic progenitor cells. The aim of this study was to examine the consequences of human HIP/PAP expression in the liver of transgenic mice. We demonstrated that HIP/PAP stimulated liver regeneration after partial hepatectomy. To further investigate the enhanced liver regeneration observed in vivo, primary cultures of hepatocytes were used to evaluate the mitogenic and anti-apoptotic properties of HIP/PAP. HIP/PAP increased hepatocyte DNA synthesis and protected hepatocytes against TNF-alpha plus actinomycin-D-induced apoptosis. HIP/PAP anti-apoptotic effects against TNF-alpha were clearly demonstrated when protein kinase A activity was specifically inhibited by KT5720, and HIP/PAP stimulated PKA-dependent phosphorylation of the proapoptotic Bad protein at Ser-112, suggesting that HIP/PAP may compete with cAMP to stimulate PKA activity. Overall, our results led us to propose a new role for a C-type lectin, HIP/PAP, as a hepatic cytokine that combines mitogenic and anti-apoptotic functions regarding hepatocytes, and consequently acts as a growth factor in vivo to enhance liver regeneration.
Simon
Marie-Therese
MT
Institut National de la Santé et de la Recherche Médicale U-370, Necker-Pasteur Institutes, Universite Paris V, 75742 Paris Cedex 15, France.
Pauloin
Alain
A
Normand
Guillaume
G
Lieu
Hanh-Tu
HT
Mouly
Helene
H
Pivert
Gerard
G
Carnot
Françoise
F
Tralhao
J Guilherme
JG
Brechot
Christian
C
Christa
Laurence
L
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000502:physiology*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D003609:Dactinomycin / Q000633:toxicity; D006498:Hepatectomy; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics / Q000502:physiology*; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008934:Mitogens / Q000502:physiology; D000073718:Pancreatitis-Associated Proteins; D010766:Phosphorylation; D011506:Proteins; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D051025:bcl-Associated Death Protein
D000951:Antigens, Neoplasm; C494819:BAD protein, human; C494820:Bad protein, mouse; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D037181:Lectins, C-Type; D008934:Mitogens; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C000612141:REG3A protein, human; C490253:Reg3b protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051025:bcl-Associated Death Protein; D003609:Dactinomycin; D012694:Serine; D004247:DNA; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases