Pifithrin-alpha induced p53 inhibition does not affect liver regeneration after partial hepatectomy in mice.
OBJECTIVE
Beside its well-known function as tumour suppressor gene, p53 is supposed to positively regulate cell division and cell differentiation. Because hepatocyte proliferation has been reported to be reduced by blockade of p53 function in vitro, we examined in the present study the impact of p53 inhibition on hepatocyte proliferation in vivo.


METHODS
Mice treated with either pifithrin-alpha (PFT), a p53-inactivating agent, or the equivalent volume of vehicle, were subjected to 70% hepatectomy. In addition to assessment of liver mass restitution we examined p53 and p21 protein expression as well as PCNA expression and BrdU incorporation by using Western blot and immunohistochemical techniques. Extent of apoptosis was assessed by TUNEL assay.


RESULTS
PFT lowered nuclear but not cytoplasmic p53, and did not inhibit protein expression of regeneration-associated p21. PCNA protein expression as well as PCNA and BrdU immunohistochemistry did not differ between regenerating livers of either PFT- or vehicle-treated animals. Moreover, TUNEL analysis of regenerated liver tissue revealed comparable numbers of apoptotic cells in both groups.


CONCLUSIONS
Pharmacological inhibition of p53 did not impair liver regeneration in mice, implying that p53 is functionally redundant in that p53-independent pathways compensate for the blockade of p53 and sufficiently support the process of hepatocyte replication in liver regeneration.
Eipel
Christian
C
Department of Experimental Surgery, University of Rostock, Schillingallee 70, 18055 Rostock, Germany.
Schuett
Harald
H
Glawe
Claudia
C
Bordel
Reingart
R
Menger
Michael D
MD
Vollmar
Brigitte
B
D000818:Animals; D017209:Apoptosis; D052160:Benzothiazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D020287:In Situ Nick-End Labeling; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism*; D014050:Toluene / Q000031:analogs & derivatives* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
D052160:Benzothiazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018809:Proliferating Cell Nuclear Antigen; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin