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PMID: 11114892 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Targeted disruption of the three Rb-related genes leads to loss of G(1) control and immortalization.

Genes & development ·Vol. 14 ·No. 23 ·2000-12-01 ·Pages 3037-50

Sage J, Mulligan GJ, Attardi LD, Miller A, Chen S, Williams B, Theodorou E, Jacks T

Abstract

The retinoblastoma protein, pRB, and the closely related proteins p107 and p130 are important regulators of the mammalian cell cycle. Biochemical and genetic studies have demonstrated overlapping as well as distinct functions for the three proteins in cell cycle control and mouse development. However, the role of the pRB family as a whole in the regulation of cell proliferation, cell death, or cell differentiation is not known. We generated embryonic stem (ES) cells and other cell types mutant for all three genes. Triple knock-out mouse embryonic fibroblasts (TKO MEFs) had a shorter cell cycle than wild-type, single, or double knock-out control cells. TKO cells were resistant to G(1) arrest following DNA damage, despite retaining functional p53 activity. They were also insensitive to G(1) arrest signals following contact inhibition or serum starvation. Finally, TKO MEFs did not undergo senescence in culture and do possess some characteristics of transformed cells. Our results confirm the essential role of the Rb family in the control of the G(1)/S transition, place the three Rb family members downstream of multiple cell cycle control pathways, and further the link between loss of cell cycle control and tumorigenesis.

MeSH Terms
Animals Cell Cycle Cell Division Cell Survival Cell Transformation, Neoplastic Cells, Cultured Culture Media, Serum-Free DNA Damage/drug effects,radiation effects Doxorubicin/pharmacology G1 Phase Gene Targeting Genes, ras Mice Mice, Inbred C57BL Mice, Knockout Nuclear Proteins/genetics,physiology Phosphoproteins/genetics,physiology Proteins Retinoblastoma Protein/genetics,physiology Retinoblastoma-Like Protein p107 Retinoblastoma-Like Protein p130
Chemicals
Culture Media, Serum-Free Nuclear Proteins Phosphoproteins Proteins Rbl1 protein, mouse Rbl2 protein, mouse Retinoblastoma Protein Retinoblastoma-Like Protein p107 Retinoblastoma-Like Protein p130 Doxorubicin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Sage J
Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Mulligan G J
Attardi L D
Miller A
Chen S
Williams B
Theodorou E
Jacks T
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.843200
Published
2000-12-01
Pages
3037-50
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC317090
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.843200 PMC Full Text View journal details
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