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TRIM3, a tumor suppressor linked to regulation of p21(Waf1/Cip1.).

Liu Y, Raheja R, Yeh N, Ciznadija D, Pedraza AM, Ozawa T, Hukkelhoven E, Erdjument-Bromage H, Tempst P, Gauthier NP, Brennan C, Holland EC, Koff A - Oncogene (2013)

Bottom Line: The TRIM family of genes is largely studied because of their roles in development, differentiation and host cell antiviral defenses; however, roles in cancer biology are emerging.Furthermore, TRIM3 can bind to the cdk inhibitor p21(WAF1/CIP1).Thus, we conclude that TRIM3 is a tumor suppressor mapping to chromosome 11p15.5 and that it might block tumor growth by sequestering p21 and preventing it from facilitating the accumulation of cyclin D1-cdk4.

View Article: PubMed Central - PubMed

Affiliation: Programs in Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

ABSTRACT
The TRIM family of genes is largely studied because of their roles in development, differentiation and host cell antiviral defenses; however, roles in cancer biology are emerging. Loss of heterozygosity of the TRIM3 locus in ∼20% of human glioblastomas raised the possibility that this NHL-domain containing member of the TRIM gene family might be a mammalian tumor suppressor. Consistent with this, reducing TRIM3 expression increased the incidence of and accelerated the development of platelet-derived growth factor -induced glioma in mice. Furthermore, TRIM3 can bind to the cdk inhibitor p21(WAF1/CIP1). Thus, we conclude that TRIM3 is a tumor suppressor mapping to chromosome 11p15.5 and that it might block tumor growth by sequestering p21 and preventing it from facilitating the accumulation of cyclin D1-cdk4.

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TRIM3 induces growth arrest(A) Immunofluorescence. YH/J12 cells were transfected with either a mock vector or a myc-TRIM3 expression plasmid and cells were labeled with 20μM BrdU for two hours, forty-eight hours after transfection. A representative image of the cells is shown in the top panel (green, αmyc, TRIM3; red, αBrdU, S-phase cell; blue, DAPI, DNA). BrdU incorporation is quantitated at the bottom of the panel and was determined from at least three independent experiments (mean ± standard deviation), for each of which 100-200 cells were counted. (B) TRIM3 induces G0/G1 arrest in human T98G glioma cells. T98G cells were transfected with myc-TRIM3 and 48 hours later were fixed and stained with propidium iodide (DNA content) and anti-myc. In this representative transfection, 14.7% of the cells were transfected with the myc-TRIM3 expression plasmid and these were uniformly arrested at G0/G1. The remaining cells were still distributed throughout the cell cycle. This experiment was repeated twice with similar results.
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Figure 6: TRIM3 induces growth arrest(A) Immunofluorescence. YH/J12 cells were transfected with either a mock vector or a myc-TRIM3 expression plasmid and cells were labeled with 20μM BrdU for two hours, forty-eight hours after transfection. A representative image of the cells is shown in the top panel (green, αmyc, TRIM3; red, αBrdU, S-phase cell; blue, DAPI, DNA). BrdU incorporation is quantitated at the bottom of the panel and was determined from at least three independent experiments (mean ± standard deviation), for each of which 100-200 cells were counted. (B) TRIM3 induces G0/G1 arrest in human T98G glioma cells. T98G cells were transfected with myc-TRIM3 and 48 hours later were fixed and stained with propidium iodide (DNA content) and anti-myc. In this representative transfection, 14.7% of the cells were transfected with the myc-TRIM3 expression plasmid and these were uniformly arrested at G0/G1. The remaining cells were still distributed throughout the cell cycle. This experiment was repeated twice with similar results.

Mentions: Other NHL containing TRIMs inhibit cell proliferation when over-expressed in various cell types, both those in which they are endogenously expressed and in heterologous cell types (reviewed in [11]). Thus, we looked at the effect of manipulating TRIM3 expression in the PDGF-transformed glial tumor cells. When we reduced the level of TRIM3 in YH/J12 cells the fraction of cycling cells increased and the amount of p21 increased (Fig. 2). Conversely BrdU incorporation was reduced significantly when TRIM3 was over-expressed (Fig. 6A). When TRIM3 was over-expressed to similar levels in p21-deficient YH/J12 cells, it did not reduce proliferation; however, proliferation in these cells is so poor it is difficult to reach a conclusion about the significance of this (data not shown). Cells in which TRIM3 was over-expressed exited the cell cycle and accumulated in G0/G1 phase (Fig. 6B). However, we could not determine if p21 levels were changed because only a fraction of the cells express TRIM3 and we could not identify any reliable immunohistochemical reagents specific for mouse p21. Thus, there is a reciprocal relationship between the expression of TRIM3 and the fraction of cells in S phase.


TRIM3, a tumor suppressor linked to regulation of p21(Waf1/Cip1.).

Liu Y, Raheja R, Yeh N, Ciznadija D, Pedraza AM, Ozawa T, Hukkelhoven E, Erdjument-Bromage H, Tempst P, Gauthier NP, Brennan C, Holland EC, Koff A - Oncogene (2013)

TRIM3 induces growth arrest(A) Immunofluorescence. YH/J12 cells were transfected with either a mock vector or a myc-TRIM3 expression plasmid and cells were labeled with 20μM BrdU for two hours, forty-eight hours after transfection. A representative image of the cells is shown in the top panel (green, αmyc, TRIM3; red, αBrdU, S-phase cell; blue, DAPI, DNA). BrdU incorporation is quantitated at the bottom of the panel and was determined from at least three independent experiments (mean ± standard deviation), for each of which 100-200 cells were counted. (B) TRIM3 induces G0/G1 arrest in human T98G glioma cells. T98G cells were transfected with myc-TRIM3 and 48 hours later were fixed and stained with propidium iodide (DNA content) and anti-myc. In this representative transfection, 14.7% of the cells were transfected with the myc-TRIM3 expression plasmid and these were uniformly arrested at G0/G1. The remaining cells were still distributed throughout the cell cycle. This experiment was repeated twice with similar results.
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Related In: Results  -  Collection

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Show All Figures
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Figure 6: TRIM3 induces growth arrest(A) Immunofluorescence. YH/J12 cells were transfected with either a mock vector or a myc-TRIM3 expression plasmid and cells were labeled with 20μM BrdU for two hours, forty-eight hours after transfection. A representative image of the cells is shown in the top panel (green, αmyc, TRIM3; red, αBrdU, S-phase cell; blue, DAPI, DNA). BrdU incorporation is quantitated at the bottom of the panel and was determined from at least three independent experiments (mean ± standard deviation), for each of which 100-200 cells were counted. (B) TRIM3 induces G0/G1 arrest in human T98G glioma cells. T98G cells were transfected with myc-TRIM3 and 48 hours later were fixed and stained with propidium iodide (DNA content) and anti-myc. In this representative transfection, 14.7% of the cells were transfected with the myc-TRIM3 expression plasmid and these were uniformly arrested at G0/G1. The remaining cells were still distributed throughout the cell cycle. This experiment was repeated twice with similar results.
Mentions: Other NHL containing TRIMs inhibit cell proliferation when over-expressed in various cell types, both those in which they are endogenously expressed and in heterologous cell types (reviewed in [11]). Thus, we looked at the effect of manipulating TRIM3 expression in the PDGF-transformed glial tumor cells. When we reduced the level of TRIM3 in YH/J12 cells the fraction of cycling cells increased and the amount of p21 increased (Fig. 2). Conversely BrdU incorporation was reduced significantly when TRIM3 was over-expressed (Fig. 6A). When TRIM3 was over-expressed to similar levels in p21-deficient YH/J12 cells, it did not reduce proliferation; however, proliferation in these cells is so poor it is difficult to reach a conclusion about the significance of this (data not shown). Cells in which TRIM3 was over-expressed exited the cell cycle and accumulated in G0/G1 phase (Fig. 6B). However, we could not determine if p21 levels were changed because only a fraction of the cells express TRIM3 and we could not identify any reliable immunohistochemical reagents specific for mouse p21. Thus, there is a reciprocal relationship between the expression of TRIM3 and the fraction of cells in S phase.

Bottom Line: The TRIM family of genes is largely studied because of their roles in development, differentiation and host cell antiviral defenses; however, roles in cancer biology are emerging.Furthermore, TRIM3 can bind to the cdk inhibitor p21(WAF1/CIP1).Thus, we conclude that TRIM3 is a tumor suppressor mapping to chromosome 11p15.5 and that it might block tumor growth by sequestering p21 and preventing it from facilitating the accumulation of cyclin D1-cdk4.

View Article: PubMed Central - PubMed

Affiliation: Programs in Molecular Biology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

ABSTRACT
The TRIM family of genes is largely studied because of their roles in development, differentiation and host cell antiviral defenses; however, roles in cancer biology are emerging. Loss of heterozygosity of the TRIM3 locus in ∼20% of human glioblastomas raised the possibility that this NHL-domain containing member of the TRIM gene family might be a mammalian tumor suppressor. Consistent with this, reducing TRIM3 expression increased the incidence of and accelerated the development of platelet-derived growth factor -induced glioma in mice. Furthermore, TRIM3 can bind to the cdk inhibitor p21(WAF1/CIP1). Thus, we conclude that TRIM3 is a tumor suppressor mapping to chromosome 11p15.5 and that it might block tumor growth by sequestering p21 and preventing it from facilitating the accumulation of cyclin D1-cdk4.

Show MeSH
Related in: MedlinePlus