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PLU-1/JARID1B/KDM5B is required for embryonic survival and contributes to cell proliferation in the mammary gland and in ER+ breast cancer cells.

Authors: Catchpole, S  Spencer-Dene, B  Hall, D  Santangelo, S  Rosewell, I  Guenatri, M  Beatson, R  Scibetta, AG  Burchell, JM  Taylor-Papadimitriou, J 
Citation: Catchpole S, etal., Int J Oncol. 2011 May;38(5):1267-77. doi: 10.3892/ijo.2011.956. Epub 2011 Feb 28.
Pubmed: (View Article at PubMed) PMID:21369698
DOI: Full-text: DOI:10.3892/ijo.2011.956

The four members of the JARID1/KDM5 family of proteins, a sub-group of the larger ARID (AT rich DNA binding domain) family, have been shown to demethylate trimethylated lysine 4 on histone 3 (H3K4me3), a chromatin mark associated with actively transcribed genes. In some lower organisms a single homologue of JARID1 is found, and functions of the four proteins found in mice and humans may be specific or overlapping. To investigate the function of the Jarid1B protein we examined the effects of deletion of the gene in mice. Systemic knock out of Jarid1b resulted in early embryonic lethality, whereas mice not expressing the related Jarid1A gene are viable and fertile. A second mouse strain expressing a Jarid1b gene with the ARID domain deleted was viable and fertile but displayed a mammary phenotype, where terminal end bud development and side branching was delayed at puberty and in early pregnancy. Since development of terminal end buds are completely dependent on signalling from the estrogen receptor (ERalpha), we investigated the expression of a target gene (progesterone receptor) in the ARID mouse and found levels to be reduced as compared to wild-type. JARID1B is widely expressed in ER+ breast cancers and breast cancer cell lines, and interaction with ERalpha was demonstrated by co-immunoprecipitations in cells transfected with tagged ERalpha and JARID1B genes. Down-regulation of expression of JARID1B using shRNAi in MCF-7 cells resulted in a dramatic decrease in E2 stimulated tumour growth in nude mice. The data demonstrate a specific role for Jarid1B in early embryonic development, in the development and differentiation of the normal mammary gland, and in estrogen induced growth of ER+ breast cancer.

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CRRD Object Information
CRRD ID: 9587774
Created: 2014-10-17
Species: All species
Last Modified: 2014-10-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.