Liver-specific pRB loss results in ectopic cell cycle entry and aberrant ploidy.
The liver exhibits an exquisitely controlled cell cycle, wherein hepatocytes are maintained in quiescence until stimulated to proliferate. The retinoblastoma tumor suppressor, pRB, plays a central role in proliferative control by inhibiting inappropriate cell cycle entry. In many cases, liver cancer arises due to aberrant cycles of proliferation, and correspondingly, pRB is functionally inactivated in the majority of hepatocellular carcinomas. Therefore, to determine how pRB loss may provide conditions permissive for deregulated hepatocyte proliferation, we investigated the consequence of somatic pRB inactivation in murine liver. We show that liver-specific pRB loss results in E2F target gene deregulation and elevated cell cycle progression during post-natal growth. However, in adult livers, E2F targets are repressed and hepatocytes become quiescent independent of pRB, suggesting that other factors may compensate for pRB loss. Therefore, to probe the consequences of acute pRB inactivation in livers of adult mice, we gave adenoviral-Cre by i.v. injection. We show that acute pRB loss is sufficient to elicit E2F target gene expression and cell cycle entry in adult liver, demonstrating a critical role for pRB in maintaining hepatocyte quiescence. Finally, we show that liver-specific pRB loss results in the development of nuclear pleomorphism associated with elevated ploidy that is evident in adult mice harboring both acute and chronic pRB loss. Together, these results show the crucial role played by pRB in maintaining hepatocyte quiescence and ploidy in adult liver in vivo and underscore the critical importance of delineating the consequences of acute pRB loss in adult animals.
Mayhew
Christopher N
CN
Department of Cell Biology, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267-0521, USA.
Bosco
Emily E
EE
Fox
Sejal R
SR
Okaya
Tomohisa
T
Tarapore
Pheruza
P
Schwemberger
Sandy J
SJ
Babcock
George F
GF
Lentsch
Alex B
AB
Fukasawa
Kenji
K
Knudsen
Erik S
ES
D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D050684:E2F Transcription Factors; D020868:Gene Silencing; D016161:Genes, Retinoblastoma / Q000235:genetics; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011003:Ploidies; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; D014157:Transcription Factors