G1 arrest and differentiation can occur independently of Rb family function.
The ability of progenitor cells to exit the cell cycle is essential for proper embryonic development and homeostasis, but the mechanisms governing cell cycle exit are still not fully understood. Here, we tested the requirement for the retinoblastoma (Rb) protein and its family members p107 and p130 in G0/G1 arrest and differentiation in mammalian cells. We found that Rb family triple knockout (TKO) mouse embryos survive until days 9-11 of gestation. Strikingly, some TKO cells, including in epithelial and neural lineages, are able to exit the cell cycle in G0/G1 and differentiate in teratomas and in culture. This ability of TKO cells to arrest in G0/G1 is associated with the repression of key E2F target genes. Thus, G1 arrest is not always dependent on Rb family members, which illustrates the robustness of cell cycle regulatory networks during differentiation and allows for the identification of candidate pathways to inhibit the expansion of cancer cells with mutations in the Rb pathway.
Department of Pediatrics, Stanford Medical School, Stanford, CA 94305, USA.
Stacey E
SE
Wirt
Adam S
AS
Adler
Véronique
V
Gebala
James M
JM
Weimann
Bethany E
BE
Schaffer
Louis A
LA
Saddic
Patrick
P
Viatour
Hannes
H
Vogel
Howard Y
HY
Chang
Alex
A
Meissner
Julien
J
Sage
D000818:Animals; D019521:Body Patterning / Q000502:physiology; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D016193:G1 Phase / Q000502:physiology*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000502:physiology; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130 / Q000235:genetics / Q000378:metabolism; D013724:Teratoma / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism
D018797:Cell Cycle Proteins; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors