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Polycomb group protein Bmi1 is required for growth of RAF driven non-small-cell lung cancer.

Becker M, Korn C, Sienerth AR, Voswinckel R, Luetkenhaus K, Ceteci F, Rapp UR - PLoS ONE (2009)

Bottom Line: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared.Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth.Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a) and p19(ARF).

View Article: PubMed Central - PubMed

Affiliation: Bayerisches Krebsforschungszentrum, University of Wuerzburg, Wuerzburg, Germany.

ABSTRACT

Background: We have previously described a RAF oncogene driven transgenic mouse model for non small cell lung cancer (NSCLC). Here we examine whether tumor initiation and growth requires the stem cell self-renewal factor Bmi1.

Principal findings: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared. Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth. As the line with shorter latency matched the life span of Bmi1 knock out mice, these mice were chosen for further study. The absence of Bmi1 did not decrease the number of tumor initiation in these mice as only the size and not the number of tumors decreased. Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a) and p19(ARF).

Significance: The data identifies Bmi1 as an important factor for expansion but not initiation of RAF driven NSCLC.

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Related in: MedlinePlus

p15INK4b, p16INK4a, p19ARF and Cbx7 expression in lungs of BXB11 and Bmi1−/−BXB11 mice.A–D) Semi-quantitative real time PCR analysis of total RNA from whole lungs of two weeks old mice, genotypes as indicated. BXB11 levels were set to one. Data are representative of two independent sets of analysis. Data show standard deviations from triplicate values. p-values were calculated using Student's t-test, only p-values indicating significance are shown. A) Quantification of p16INK4a expression levels B) Quantification of p19ARF RNA expression levels. C) Quantification of p15INK4b expression levels. D) Quantification of Cbx7 expression levels.
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pone-0004230-g004: p15INK4b, p16INK4a, p19ARF and Cbx7 expression in lungs of BXB11 and Bmi1−/−BXB11 mice.A–D) Semi-quantitative real time PCR analysis of total RNA from whole lungs of two weeks old mice, genotypes as indicated. BXB11 levels were set to one. Data are representative of two independent sets of analysis. Data show standard deviations from triplicate values. p-values were calculated using Student's t-test, only p-values indicating significance are shown. A) Quantification of p16INK4a expression levels B) Quantification of p19ARF RNA expression levels. C) Quantification of p15INK4b expression levels. D) Quantification of Cbx7 expression levels.

Mentions: Bmi1 is implicated in cdki regulation. Most prominently p16INK4a, p19ARF have been shown to be negatively regulated by Bmi1 [27]. Therefore altered p16INK4a/p19ARF expression levels could account for the reduced number of surviving and cycling cells in Bmi1−/−BXB11 tumors. We first analyzed expression of mRNA levels of p16INK4a by semi-quantitative RTPCR in lungs of two weeks old BXB11 and Bmi1−/−BXB11 mice (Figure 4A). Expression levels of p16INK4a were markedly increased in Bmi1−/−BXB11 lungs. Western blot analysis of whole lung lysates confirmed this result on the protein level (Figure S6A).


Polycomb group protein Bmi1 is required for growth of RAF driven non-small-cell lung cancer.

Becker M, Korn C, Sienerth AR, Voswinckel R, Luetkenhaus K, Ceteci F, Rapp UR - PLoS ONE (2009)

p15INK4b, p16INK4a, p19ARF and Cbx7 expression in lungs of BXB11 and Bmi1−/−BXB11 mice.A–D) Semi-quantitative real time PCR analysis of total RNA from whole lungs of two weeks old mice, genotypes as indicated. BXB11 levels were set to one. Data are representative of two independent sets of analysis. Data show standard deviations from triplicate values. p-values were calculated using Student's t-test, only p-values indicating significance are shown. A) Quantification of p16INK4a expression levels B) Quantification of p19ARF RNA expression levels. C) Quantification of p15INK4b expression levels. D) Quantification of Cbx7 expression levels.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2626631&req=5

pone-0004230-g004: p15INK4b, p16INK4a, p19ARF and Cbx7 expression in lungs of BXB11 and Bmi1−/−BXB11 mice.A–D) Semi-quantitative real time PCR analysis of total RNA from whole lungs of two weeks old mice, genotypes as indicated. BXB11 levels were set to one. Data are representative of two independent sets of analysis. Data show standard deviations from triplicate values. p-values were calculated using Student's t-test, only p-values indicating significance are shown. A) Quantification of p16INK4a expression levels B) Quantification of p19ARF RNA expression levels. C) Quantification of p15INK4b expression levels. D) Quantification of Cbx7 expression levels.
Mentions: Bmi1 is implicated in cdki regulation. Most prominently p16INK4a, p19ARF have been shown to be negatively regulated by Bmi1 [27]. Therefore altered p16INK4a/p19ARF expression levels could account for the reduced number of surviving and cycling cells in Bmi1−/−BXB11 tumors. We first analyzed expression of mRNA levels of p16INK4a by semi-quantitative RTPCR in lungs of two weeks old BXB11 and Bmi1−/−BXB11 mice (Figure 4A). Expression levels of p16INK4a were markedly increased in Bmi1−/−BXB11 lungs. Western blot analysis of whole lung lysates confirmed this result on the protein level (Figure S6A).

Bottom Line: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared.Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth.Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a) and p19(ARF).

View Article: PubMed Central - PubMed

Affiliation: Bayerisches Krebsforschungszentrum, University of Wuerzburg, Wuerzburg, Germany.

ABSTRACT

Background: We have previously described a RAF oncogene driven transgenic mouse model for non small cell lung cancer (NSCLC). Here we examine whether tumor initiation and growth requires the stem cell self-renewal factor Bmi1.

Principal findings: In order to evaluate Bmi1 function in NSCLC two founder lines that differ in incidence and latency of tumor formation were compared. Ablation of Bmi1 expression in both lines had a dramatically decreased tumor growth. As the line with shorter latency matched the life span of Bmi1 knock out mice, these mice were chosen for further study. The absence of Bmi1 did not decrease the number of tumor initiation in these mice as only the size and not the number of tumors decreased. Reduction in tumor growth resulted from an increase in cell death and decrease in cell cycle progression that corresponded with up-regulation of the p16(INK4a) and p19(ARF).

Significance: The data identifies Bmi1 as an important factor for expansion but not initiation of RAF driven NSCLC.

Show MeSH
Related in: MedlinePlus