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Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis.

Lomonosov M, Meziane el K, Ye H, Nelson DE, Randle SJ, Laman H - PLoS ONE (2011)

Bottom Line: Here we present new evidence in vitro and in vivo on the oncogenic potential of this regulatory protein in primary haematopoietic stem and progenitor cells (HSPCs).Increasing Fbxo7 expression in HSPCs suppressed their colony forming ability in vitro, specifically decreasing CD11b (Mac1) expression, and these effects were dependent on an intact p53 pathway.Furthermore, increased Fbxo7 levels enhanced the proliferative capacity of p53 HSPCs when they were grown in reduced concentrations of stem cell factor.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

ABSTRACT
Fbxo7 is an unusual F box protein that augments D-type cyclin complex formation with Cdk6, but not Cdk4 or Cdk2, and its over-expression has been demonstrated to transform immortalised fibroblasts in a Cdk6-dependent manner. Here we present new evidence in vitro and in vivo on the oncogenic potential of this regulatory protein in primary haematopoietic stem and progenitor cells (HSPCs). Increasing Fbxo7 expression in HSPCs suppressed their colony forming ability in vitro, specifically decreasing CD11b (Mac1) expression, and these effects were dependent on an intact p53 pathway. Furthermore, increased Fbxo7 levels enhanced the proliferative capacity of p53 HSPCs when they were grown in reduced concentrations of stem cell factor. Finally, irradiated mice reconstituted with p53 , but not wild-type, HSPCs expressing Fbxo7 showed a statistically significant increase in the incidence of T cell lymphoma in vivo. These data argue that Fbxo7 negatively regulates the proliferation and differentiation of HSPCs in a p53-dependent manner, and that in the absence of p53, Fbxo7 expression can promote T cell lymphomagenesis.

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Fbxo7 acts as a proliferative factor in p53 s grown in reduced SCF.(A) Table of the quantification of colony number of WT and p53  cells grown at different concentrations of SCF. (B) Graphs of the total cell number at three concentrations of SCF in WT and p53  cells expressing Fbxo7 compared to MSCV. (C) Graph of ratio of the number of either WT or p53  cells expressing Fbxo7 compared to MSCV at different concentrations of SCF. In these experiments, the error is represented as the SD, and quantification is of three independent experiments.
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pone-0021165-g004: Fbxo7 acts as a proliferative factor in p53 s grown in reduced SCF.(A) Table of the quantification of colony number of WT and p53 cells grown at different concentrations of SCF. (B) Graphs of the total cell number at three concentrations of SCF in WT and p53 cells expressing Fbxo7 compared to MSCV. (C) Graph of ratio of the number of either WT or p53 cells expressing Fbxo7 compared to MSCV at different concentrations of SCF. In these experiments, the error is represented as the SD, and quantification is of three independent experiments.

Mentions: As SCF can act as a survival factor for progenitor cells with only limited effects as a mitogen [23], we next tested whether increasing Fbxo7 expression could compensate for reduced SCF signalling. In these experiments, the concentration of SCF was reduced, while FCS, IL-3 and IL-6 concentrations were maintained. As expected, the number and size of colonies formed by WT HSPCs was reduced when the SCF was decreased from 50 ng/mL (standard conditions) to 20 or 8 ng/mL (Figure 4A), and consistent with our results in Figure 1C, Fbxo7 reduced the number of WT HSPCs colonies under standard growth conditions. However, at lower SCF concentrations, Fbxo7 expression did not significantly alter the number of colonies formed by WT HSPCs (Figure 4A) or the total number of WT cells that grew (Figure 4B, C). We conclude that Fbxo7 exerts its inhibitory effect on colony formation at a threshold concentration of SCF above 20 ng/mL and that increased Fbxo7 expression did not substitute for reduced SCF signalling.


Expression of Fbxo7 in haematopoietic progenitor cells cooperates with p53 loss to promote lymphomagenesis.

Lomonosov M, Meziane el K, Ye H, Nelson DE, Randle SJ, Laman H - PLoS ONE (2011)

Fbxo7 acts as a proliferative factor in p53 s grown in reduced SCF.(A) Table of the quantification of colony number of WT and p53  cells grown at different concentrations of SCF. (B) Graphs of the total cell number at three concentrations of SCF in WT and p53  cells expressing Fbxo7 compared to MSCV. (C) Graph of ratio of the number of either WT or p53  cells expressing Fbxo7 compared to MSCV at different concentrations of SCF. In these experiments, the error is represented as the SD, and quantification is of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3117880&req=5

pone-0021165-g004: Fbxo7 acts as a proliferative factor in p53 s grown in reduced SCF.(A) Table of the quantification of colony number of WT and p53 cells grown at different concentrations of SCF. (B) Graphs of the total cell number at three concentrations of SCF in WT and p53 cells expressing Fbxo7 compared to MSCV. (C) Graph of ratio of the number of either WT or p53 cells expressing Fbxo7 compared to MSCV at different concentrations of SCF. In these experiments, the error is represented as the SD, and quantification is of three independent experiments.
Mentions: As SCF can act as a survival factor for progenitor cells with only limited effects as a mitogen [23], we next tested whether increasing Fbxo7 expression could compensate for reduced SCF signalling. In these experiments, the concentration of SCF was reduced, while FCS, IL-3 and IL-6 concentrations were maintained. As expected, the number and size of colonies formed by WT HSPCs was reduced when the SCF was decreased from 50 ng/mL (standard conditions) to 20 or 8 ng/mL (Figure 4A), and consistent with our results in Figure 1C, Fbxo7 reduced the number of WT HSPCs colonies under standard growth conditions. However, at lower SCF concentrations, Fbxo7 expression did not significantly alter the number of colonies formed by WT HSPCs (Figure 4A) or the total number of WT cells that grew (Figure 4B, C). We conclude that Fbxo7 exerts its inhibitory effect on colony formation at a threshold concentration of SCF above 20 ng/mL and that increased Fbxo7 expression did not substitute for reduced SCF signalling.

Bottom Line: Here we present new evidence in vitro and in vivo on the oncogenic potential of this regulatory protein in primary haematopoietic stem and progenitor cells (HSPCs).Increasing Fbxo7 expression in HSPCs suppressed their colony forming ability in vitro, specifically decreasing CD11b (Mac1) expression, and these effects were dependent on an intact p53 pathway.Furthermore, increased Fbxo7 levels enhanced the proliferative capacity of p53 HSPCs when they were grown in reduced concentrations of stem cell factor.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

ABSTRACT
Fbxo7 is an unusual F box protein that augments D-type cyclin complex formation with Cdk6, but not Cdk4 or Cdk2, and its over-expression has been demonstrated to transform immortalised fibroblasts in a Cdk6-dependent manner. Here we present new evidence in vitro and in vivo on the oncogenic potential of this regulatory protein in primary haematopoietic stem and progenitor cells (HSPCs). Increasing Fbxo7 expression in HSPCs suppressed their colony forming ability in vitro, specifically decreasing CD11b (Mac1) expression, and these effects were dependent on an intact p53 pathway. Furthermore, increased Fbxo7 levels enhanced the proliferative capacity of p53 HSPCs when they were grown in reduced concentrations of stem cell factor. Finally, irradiated mice reconstituted with p53 , but not wild-type, HSPCs expressing Fbxo7 showed a statistically significant increase in the incidence of T cell lymphoma in vivo. These data argue that Fbxo7 negatively regulates the proliferation and differentiation of HSPCs in a p53-dependent manner, and that in the absence of p53, Fbxo7 expression can promote T cell lymphomagenesis.

Show MeSH
Related in: MedlinePlus