Dataset Information

Induction of functional Brm protein from Brm knockout mice.

ABSTRACT: Once the knockout of the Brm gene was found to be nontumorigenic in mice, the study of BRM's involvement in cancer seemed less important compared with that of its homolog, Brg1. This has likely contributed to the disparity that has been observed in the publication ratio between BRG1 and BRM. We show that a previously published Brm knockout mouse is an incomplete knockout whereby a truncated isoform of Brm is detected in normal tissue and in tumors. We show that this truncated Brm isoform has functionality comparable to wild type Brm. By immunohistochemistry (IHC), this truncated Brm is undetectable in normal lung tissue and is minimal to very low in Brmnull tumors. However, it is significant in a subset (~40%) of Brg1/Brm double knockout (DKO) tumors that robustly express this truncated BRM, which in part stems from an increase in Brm mRNA levels. Thus, it is likely that this mutant mouse model does not accurately reflect the role that Brm plays in cancer development. We suggest that the construction of a completely new mouse Brm knockout, where Brm is functionally absent, is needed to determine whether or not Brm is actually tumorigenic and if Brm might be a tumor suppressor.

SUBMITTER: Thompson KW

PROVIDER: S-EPMC4468321 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Induction of functional Brm protein from Brm knockout mice.

Thompson Kenneth W KW Marquez Stefanie B SB Lu Li L Reisman David D

Oncoscience 20150418 4

Once the knockout of the Brm gene was found to be nontumorigenic in mice, the study of BRM's involvement in cancer seemed less important compared with that of its homolog, Brg1. This has likely contributed to the disparity that has been observed in the publication ratio between BRG1 and BRM. We show that a previously published Brm knockout mouse is an incomplete knockout whereby a truncated isoform of Brm is detected in normal tissue and in tumors. We show that this truncated Brm isoform has fun ...[more]

PMID: 26097869

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Project description:Background and aimsBone morphogenetic proteins BMP2 and BMP6 play key roles in systemic iron homeostasis by regulating production of the iron hormone hepcidin. The homeostatic iron regulator (HFE) also regulates hepcidin through a mechanism that intersects with the BMP-mothers against decapentaplegic homolog 1/5/8 (SMAD1/5/8) pathway. However, the relative roles of BMP2 compared with BMP6 and whether HFE regulates hepcidin through a BMP2-dependent mechanism remain uncertain.Approach and resultsWe therefore examined the iron phenotype of mice deficient for both Bmp2 and Bmp6 or both Bmp2 and Hfe compared with single knockout (KO) mice and littermate controls. Eight-week-old double endothelial Bmp6/Bmp2 KO mice exhibited a similar degree of hepcidin deficiency, serum iron overload, and tissue iron overload compared with single KO mice. Notably, dietary iron loading still induced liver SMAD5 phosphorylation and hepcidin in double Bmp6/endothelial Bmp2 KO mice, although no other BMP ligand mRNAs were increased in the livers of double KO mice, and only Bmp6 and Bmp2 mRNA were induced by dietary iron loading in wild-type mice. In contrast, double Hfe/endothelial Bmp2 KO mice exhibited reduced hepcidin and increased extrahepatic iron loading compared to single Hfe or endothelial Bmp2 KO mice. Liver phosphorylated SMAD5 and the SMAD1/5/8 target inhibitor of DNA binding 1 (Id1) mRNA were also reduced in double Hfe/endothelial Bmp2 KO compared with single endothelial Bmp2 KO female mice. Finally, hepcidin and Id1 mRNA induction by homodimeric BMP2, homodimeric BMP6, and heterodimeric BMP2/6 were blunted in Hfe KO primary hepatocytes.ConclusionsThese data suggest that BMP2 and BMP6 work collaboratively to regulate hepcidin expression, that BMP2-independent and BMP6-independent SMAD1/5/8 signaling contributes a nonredundant role to hepcidin regulation by iron, and that HFE regulates hepcidin at least in part through a BMP2-independent but SMAD1/5/8-dependent mechanism.

Dataset Information

Induction of functional Brm protein from Brm knockout mice.

Publications

Induction of functional Brm protein from Brm knockout mice.

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