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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 expression is reduced in some human GBM(A) Expression of TRIM3 mRNA (y-axis) relative to the DNA copy number (x-axis) in 203 GBM samples. Data were downloaded from MSKCC's Cancer Genomics Data Portal (http://cbio.mskcc.org/cancergenomics-dataportal) and samples were separated by the DNA copy number status of 11p15.5 (the TRIM3 containing locus). Deletion and gain calls were determined by the RAE algorithm [55]. Of the 91 samples that were subjected to DNA sequencing, two that exhibited a neutral DNA copy number calls of the 11p15.5 locus contained missense mutations in TRIM3. These mutations, G317S and C736Y and their mRNA expression are indicated in the chart. (B) Immunoblot. The expression of TRIM3 was examined in extracts prepared from 11 individual tumors (indicated above each lane). Tubulin is a loading control. The asterik marks the TRIM3 band.
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Figure 1: TRIM3 expression is reduced in some human GBM(A) Expression of TRIM3 mRNA (y-axis) relative to the DNA copy number (x-axis) in 203 GBM samples. Data were downloaded from MSKCC's Cancer Genomics Data Portal (http://cbio.mskcc.org/cancergenomics-dataportal) and samples were separated by the DNA copy number status of 11p15.5 (the TRIM3 containing locus). Deletion and gain calls were determined by the RAE algorithm [55]. Of the 91 samples that were subjected to DNA sequencing, two that exhibited a neutral DNA copy number calls of the 11p15.5 locus contained missense mutations in TRIM3. These mutations, G317S and C736Y and their mRNA expression are indicated in the chart. (B) Immunoblot. The expression of TRIM3 was examined in extracts prepared from 11 individual tumors (indicated above each lane). Tubulin is a loading control. The asterik marks the TRIM3 band.

Mentions: TRIM3 is encoded in the chromosomal locus 11p15.5. Loss of heterozygosity encompassing this region is observed in approximately 20% of human GBM, suggesting that TRIM3 might be a tumor suppressor gene [8]. Supporting this hypothesis of TRIM3 function, the loss of a Drosophilia ortholog of the TRIM-NHL family, brat, results in an increase in the number of secondary neuroblasts at the expense of ganglion mother cells. As comparable progenitors are found in the developing brain of mammals (reviewed in [12]) we re-analyzed 203 tumors in the TCGA study [2, 33] for TRIM3 expression, copy number, and mutation. Twenty-six of these tumors had loss of heterozygosity, two of these tumors had homozygous deletion, and three had low-level amplification of this locus. mRNA expression was correlated to gene expression (Fig. 1A). Additionally, in ninety-one tumors in which the locus was completely sequenced we identified two non-recurrent missense mutations (Fig. 1A). One of these, C736Y, is in the NHL domain and the other, G371S, is in the ABP/filamin domain.


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 expression is reduced in some human GBM(A) Expression of TRIM3 mRNA (y-axis) relative to the DNA copy number (x-axis) in 203 GBM samples. Data were downloaded from MSKCC's Cancer Genomics Data Portal (http://cbio.mskcc.org/cancergenomics-dataportal) and samples were separated by the DNA copy number status of 11p15.5 (the TRIM3 containing locus). Deletion and gain calls were determined by the RAE algorithm [55]. Of the 91 samples that were subjected to DNA sequencing, two that exhibited a neutral DNA copy number calls of the 11p15.5 locus contained missense mutations in TRIM3. These mutations, G317S and C736Y and their mRNA expression are indicated in the chart. (B) Immunoblot. The expression of TRIM3 was examined in extracts prepared from 11 individual tumors (indicated above each lane). Tubulin is a loading control. The asterik marks the TRIM3 band.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928554&req=5

Figure 1: TRIM3 expression is reduced in some human GBM(A) Expression of TRIM3 mRNA (y-axis) relative to the DNA copy number (x-axis) in 203 GBM samples. Data were downloaded from MSKCC's Cancer Genomics Data Portal (http://cbio.mskcc.org/cancergenomics-dataportal) and samples were separated by the DNA copy number status of 11p15.5 (the TRIM3 containing locus). Deletion and gain calls were determined by the RAE algorithm [55]. Of the 91 samples that were subjected to DNA sequencing, two that exhibited a neutral DNA copy number calls of the 11p15.5 locus contained missense mutations in TRIM3. These mutations, G317S and C736Y and their mRNA expression are indicated in the chart. (B) Immunoblot. The expression of TRIM3 was examined in extracts prepared from 11 individual tumors (indicated above each lane). Tubulin is a loading control. The asterik marks the TRIM3 band.
Mentions: TRIM3 is encoded in the chromosomal locus 11p15.5. Loss of heterozygosity encompassing this region is observed in approximately 20% of human GBM, suggesting that TRIM3 might be a tumor suppressor gene [8]. Supporting this hypothesis of TRIM3 function, the loss of a Drosophilia ortholog of the TRIM-NHL family, brat, results in an increase in the number of secondary neuroblasts at the expense of ganglion mother cells. As comparable progenitors are found in the developing brain of mammals (reviewed in [12]) we re-analyzed 203 tumors in the TCGA study [2, 33] for TRIM3 expression, copy number, and mutation. Twenty-six of these tumors had loss of heterozygosity, two of these tumors had homozygous deletion, and three had low-level amplification of this locus. mRNA expression was correlated to gene expression (Fig. 1A). Additionally, in ninety-one tumors in which the locus was completely sequenced we identified two non-recurrent missense mutations (Fig. 1A). One of these, C736Y, is in the NHL domain and the other, G371S, is in the ABP/filamin domain.

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