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The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance

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Abstract

Birt–Hogg–Dubé syndrome (BHD) is a rare, inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors and spontaneous pneumothorax. The BHD locus was mapped to chromosome 17p11.2 by linkage analysis, and germline mutations in a novel gene (BHD) were identified in a panel of BHD families. Using RNA interference to decrease expression of the Drosophila BHD homolog (DBHD), we have demonstrated that DBHD is required for male germline stem cell (GSC) maintenance in the fly testis. Reduction of DBHD gene activity suppresses the GSC overproliferation phenotype associated with overexpression of either unpaired (upd) or decapentaplegic (dpp). Further genetic interaction experiments suggest that DBHD regulates GSC maintenance downstream or in parallel of the JAK/STAT and Dpp signal-transduction pathways. These findings suggest that the BHD protein may regulate tumorigenesis through modulating stem cells in human.

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Acknowledgements

We thank C Dearolf, T Xie, S DiNardo, K Basler, T Neufeld, and the Bloomington Stock Center for fly stocks; R Lehmann and the Developmental Study Hybridoma Bank for antibodies; S Wincovith, S Garfield, E Cho, and S Lockett for help on the confocal microscope; H Shin for generating transgene lines; N Parrish for help on preparation of the manuscript. This research was supported by the Intramural Research Program of NIH, National Cancer Institute and by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-C0-12400.The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

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Author notes

  1. S R Singh and W Zhen: These authors contributed equally to this work.

Authors and Affiliations

  1. Mouse Cancer Genetics Program, National Institutes of Health, National Cancer Institute at Frederick, Frederick, MD, USA

    S R Singh, H Wang, S-W Oh, W Liu & S X Hou

  2. The Laboratory of Immunobiology, National Institutes of Health, National Cancer Institute at Frederick, Frederick, MD, USA

    W Zhen & B Zbar

  3. Basic Research Program, SAIC-Frederick Inc., National Cancer Institute at Frederick, Frederick, MD, USA

    Z Zheng & L S Schmidt

Authors
  1. S R Singh
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  2. W Zhen
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  3. Z Zheng
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  4. H Wang
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  5. S-W Oh
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  6. W Liu
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  7. B Zbar
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  8. L S Schmidt
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  9. S X Hou
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Correspondence to S R Singh or S X Hou.

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Singh, S., Zhen, W., Zheng, Z. et al. The Drosophila homolog of the human tumor suppressor gene BHD interacts with the JAK-STAT and Dpp signaling pathways in regulating male germline stem cell maintenance. Oncogene 25, 5933–5941 (2006). https://doi.org/10.1038/sj.onc.1209593

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