Induction of apoptosis in Mv1Lu cells by expression of competitive RB1 mutants

Whitaker, Laura; Hansen, Marc F.

doi:10.1038/sj.onc.1201277

Cited by 6 publications

(4 citation statements)

References 57 publications

(62 reference statements)

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“…It was previously shown that the amino-terminus of human Rb alone cannot localize to the nucleus without an added nuclear localization signal [29]. However, data presented above suggested that Drosophila Rbf1 might be tethered to chromatin independently of dE2F by association with other nuclear proteins.…”

Section: Resultsmentioning

confidence: 90%

The N-Terminal Domain of the Drosophila Retinoblastoma Protein Rbf1 Interacts with ORC and Associates with Chromatin in an E2F Independent Manner

2008

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BackgroundThe retinoblastoma (Rb) tumor suppressor protein can function as a DNA replication inhibitor as well as a transcription factor. Regulation of DNA replication may occur through interaction of Rb with the origin recognition complex (ORC).Principal FindingsWe characterized the interaction of Drosophila Rb, Rbf1, with ORC. Using expression of proteins in Drosophila S2 cells, we found that an N-terminal Rbf1 fragment (amino acids 1–345) is sufficient for Rbf1 association with ORC but does not bind to dE2F1. We also found that the C-terminal half of Rbf1 (amino acids 345–845) interacts with ORC. We observed that the amino-terminal domain of Rbf1 localizes to chromatin in vivo and associates with chromosomal regions implicated in replication initiation, including colocalization with Orc2 and acetylated histone H4.Conclusions/SignificanceOur results suggest that Rbf1 can associate with ORC and chromatin through domains independent of the E2F binding site. We infer that Rbf1 may play a role in regulating replication directly through its association with ORC and/or chromatin factors other than E2F. Our data suggest an important role for retinoblastoma family proteins in cell proliferation and tumor suppression through interaction with the replication initiation machinery.

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Section: Resultsmentioning

confidence: 90%

The N-Terminal Domain of the Drosophila Retinoblastoma Protein Rbf1 Interacts with ORC and Associates with Chromatin in an E2F Independent Manner

2008

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“…However, unlike the case for pRb, the relationship of those other proteins to apoptosis remains unclear. In a more direct approach, induction of apoptosis was seen in epithelial cells overexpressing a putative dominant negative pRb mutant (Whitaker and Hansen, 1997). pRb dysfunction thus appears to promote apoptosis, and in certain circumstances this effect is dependent on the presence of functional wt p53 (White, 1994).…”

Section: Discussionmentioning

confidence: 99%

p53 facilitates pRb cleavage in IL-3-deprived cells: novel pro-apoptotic activity of p53

Gottlieb

Oren

1998

The EMBO Journal

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In the interleukin-3 (IL-3)-dependent lymphoid cell line DA-1, functional p53 is required for efficient apoptosis in response to IL-3 withdrawal. Activation of p53 in these cells, by either DNA damage or p53 overexpression, results in a vital growth arrest in the presence of IL-3 and in accelerated apoptosis in its absence. Thus, IL-3 can control the choice between p53-dependent cell-cycle arrest and apoptosis. Here we report that the cross-talk between p53 and IL-3 involves joint control of pRb cleavage and degradation. Depletion of IL-3 results in caspase-mediated pRb cleavage, occurring preferentially within cells which express functional p53. Moreover, pRb can be cleaved efficiently by extracts prepared from DA-1 cells but not from their derivatives which lack p53 function. Inactivation of pRb through expression of the human papillomavirus (HPV) E7 oncogene overrides the effect of IL-3 in a p53-dependent manner. Our data suggest a novel role for p53 in the regulation of cell death and a novel mechanism for the cooperation between p53 and survival factor deprivation. Thus, p53 makes cells permissive to pRb cleavage, probably by controlling the potential activity of a pRb-cleaving caspase, whereas IL-3 withdrawal provides signals that turn on this potential activity and lead to the actual cleavage and subsequent degradation of pRb. Elimination of a presumptive anti-apoptotic effect of pRb may then facilitate conversion of p53-mediated growth arrest into apoptosis.

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“…However, these alleles encode proteins that contain multiple interaction defects. Furthermore, there has been relatively limited use of gain-of-function and dominant negative alleles of RB-1 to help clarify its function despite efforts to develop these reagents [ 31 - 35 ]. Instead, a number of tumor derived RB-1 mutants have actually emerged as excellent negative controls!…”

Section: Nature's Bounty; Using Tumor-derived Mutations In mentioning

confidence: 99%

Structure-function analysis of the retinoblastoma tumor suppressor protein – is the whole a sum of its parts?

Dick

2007

Cell Div

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Biochemical analysis of the retinoblastoma protein's function has received considerable attention since it was cloned just over 20 years ago. During this time pRB has emerged as a key regulator of the cell division cycle and its ability to block proliferation is disrupted in the vast majority of human cancers. Much has been learned about the regulation of E2F transcription factors by pRB in the cell cycle. However, many questions remain unresolved and researchers continue to explore this multifunctional protein. In particular, understanding how its biochemical functions contribute to its role as a tumor suppressor remains to be determined. Since pRB has been shown to function as an adaptor molecule that links different proteins together, or to particular promoters, analyzing pRB by disrupting individual protein interactions holds tremendous promise in unraveling the intricacies of its function. Recently, crystal structures have reported how pRB interacts with some of its molecular partners. This information has created the possibility of rationally separating pRB functions by studying mutants that disrupt individual binding sites. This review will focus on literature that investigates pRB by isolating functions based on binding sites within the pocket domain. This article will also discuss the prospects for using this approach to further explore the unknown functions of pRB.

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Induction of apoptosis in Mv1Lu cells by expression of competitive RB1 mutants

Cited by 6 publications

References 57 publications

The N-Terminal Domain of the Drosophila Retinoblastoma Protein Rbf1 Interacts with ORC and Associates with Chromatin in an E2F Independent Manner

The N-Terminal Domain of the Drosophila Retinoblastoma Protein Rbf1 Interacts with ORC and Associates with Chromatin in an E2F Independent Manner

p53 facilitates pRb cleavage in IL-3-deprived cells: novel pro-apoptotic activity of p53

Structure-function analysis of the retinoblastoma tumor suppressor protein – is the whole a sum of its parts?

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