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

By Julien Sage, G. J. Mulligan, L. Attardi, Abigail L Miller, Siqi Chen, B. Williams, E. Theodorou, T. Jacks. Genes & Development, 2000

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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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/927b0f667908711381575f664b882d0c6b0501ee

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Citations in the corpus

Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice (2001, background): “MEFs mutated in components of the Rb1 or Trp53 pathways are defective in various aspects of proliferative control, displaying altered proliferation rates, cell-cycle distributions and cell size compared with wild-type cell”
The signals and pathways activating cellular senescence. (2005, background): “Cells carrying a null mutation in the Rb gene senesce normally, yet inactivation of additional Rb family members – p107 and p130 – is sufficient to prevent senescence (Dannenberg et al., 2000; Sage et al., 2000).”
Senescence impairs successful reprogramming to pluripotent stem cells. (2009, background): “In addition, MEFs from transgenic mice generated by disruption of all Rb family proteins (Rb, p107 and p130) do not senesce (Dannenberg et al., 2000; Sage et al., 2000), suggesting that, in mice, Rb function can be compensated by Rb related proteins.”
The essence of senescence. (2010, background): “Senescence of MEFs can be bypassed also by inactivation of p53 or simultaneous ablation of RB family genes (Tanaka et al. 1994; Dannenberg et al. 2000; Sage et al. 2000).”
Comparative biology of mouse versus human cells: modelling human cancer in mice (2003, background): “Senescent MEFs also show an increase in the levels of Ink4a; however, MEFs from Ink4a -null or Rb -null embryos succumb to both culture- and RAS -induced senescenc”
The RB and p53 pathways in cancer. (2002, background): “MEFs lacking all three Rb family proteins do not senesce in culture CANCER CELL : AUGUST 2002 107 and are resistant to p19Arf-induced cell cycle arrest (Dannenberg et al., 2000; Sage et al., 2000).”
Species- and cell type-specific requirements for cellular transformation. (2004, background): “The resultant cells growth arrest, consistent with the behavior of triple knockout MEFs (i.e., pRb / , p130 / , p107 / ) (Sage et al., 2000).”
How cells coordinate growth and division. (2004, background): “Correspondingly, increasing the rate of cell cycle progression does not accelerate mass accumulation, thus resulting in abnormally small cell size [18,35,37–41].”
E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. (2002, background): “This finding is also intriguing in light of previous reports implicating an essential role for both p53 and the pRB family in the G1 DNA damage arrest checkpoint (Harrington et al. 1998; Dannenberg et al. 2000; Sage et al. 2000).”
Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis (2001, result): “These data are reminiscent of results from several other group”