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

Singh, Shree Ram; Wei, Zhen; Zheng, Zhi-Ming; Wang, H.; Oh, Su-Wan; Liu, W.; Zbar, Berton; Schmidt, Laura S.; Hou, Steven X.

doi:10.1038/sj.onc.1209593

Cited by 51 publications

(36 citation statements)

References 28 publications

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“…In Drosophila homologue (DBHD) of the human BHD, folliculin was shown to be required for male germline stem cell maintenance in the fly testis [15]. We speculate here that these results, along with our findings of low-level chromosomal instability (CIN) in oncocytoma and peripheral lymphocytes, may point to a hitherto unrecognized role of the FLCN gene product in maintenance of chromosomal stability.…”

Section: Discussionsupporting

confidence: 51%

Novel intronic germline FLCN gene mutation in a patient with multiple ipsilateral renal neoplasms

et al. 2009

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Section: Discussionsupporting

confidence: 51%

Novel intronic germline FLCN gene mutation in a patient with multiple ipsilateral renal neoplasms

et al. 2009

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“…First, gbb transcription is not affected under the same experimental conditions that cause an increase in dpp mRNA levels. Second, it has been suggested that dpp might function downstream of, or in parallel to, Jak/Stat signalling in Drosophila testes (Singh et al, 2006). Finally, the ectopic expression of Upd in eye discs results in a slight enhancement of dpp mRNA levels (Bach et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Jak/Stat signalling in niche support cells regulatesdpptranscription to control germline stem cell maintenance in theDrosophilaovary

2008

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The existence of specialised regulatory microenvironments or niches that sustain stable stem cell populations is well documented in many tissues. However, the specific mechanisms by which niche support (or stromal) cells govern stem cell maintenance remain largely unknown. Here we demonstrate that removal of the Jak/Stat pathway in support cells of the Drosophila ovarian niche leads to germline stem cell loss by differentiation. Conversely, ectopic Jak/Stat activation in support cells induces stem cell tumours, implying the presence of a signal relay between the stromal compartment and the stem cell population. We further show that ectopic Jak/Stat signalling in support cells augments dpp mRNA levels and increases the range of Dpp signalling, a Bmp2 orthologue known to act as a niche extrinsic factor required for female germline stem cell survival and division. Our results provide strong evidence for a model in which Jak/Stat signalling in somatic support cells regulates dpp transcription to define niche size and to maintain the adjacent germline stem cells in an undifferentiated state.

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“…16 Furthermore, deletion of the FLCN homolog in fruit flies disrupts male germ line stem cell maintenance, a defect that appears to be linked to the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway. 17 Two folliculin interacting proteins, FNIP1 and FNIP2, were recently isolated. [7][8][9] These factors are broadly expressed in human tissues and specifically associate with folliculin C-terminal domain in ex vivo studies.…”

Section: Introductionmentioning

confidence: 99%

The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development

Keller²,

Sun

et al. 2012

Blood

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Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1 ؊/؊ mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspaseinduced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1 ؊/؊ mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTORdependent and independent pathways. (Blood. 2012;120(6):1254-1261) IntroductionHuman Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant hereditary cancer syndrome characterized by the development of cutaneous fibrofolliculoma, multiple pulmonary cysts, spontaneous pneumothorax, and increased risk of renal cell neoplasia. 1,2 Affected individuals carry germ line mutations in FLCN, a recently characterized gene that encodes a 64-kDa protein, folliculin. 2 In kidney tumors, the FLCN wild-type (WT) allele is deleted by somatic mutation or loss of heterozygosity, [3][4][5] supporting the idea that FLCN is a classic tumor suppressor gene that follows the Knudson 2-hit hypothesis. 6 FLCN lacks predicted functional domains or homology to known proteins; however, it is also highly conserved across species indicating that it might play an essential role in development. 2 In agreement with this notion, homozygous loss of Flcn in mice causes visceral endoderm defects and embryonic lethality at E5.5-E6.5. 5 Although its precise in vivo function is unknown, folliculin may regulate cellular energy sensing by controlling mTOR signaling. [7][8][9][10] For instance, loss of Flcn in mouse kidneys leads to cellular hyperproliferation and overactivation of mTORC1, mTORC2, and MAPK pathways, whereas rapamycin treatment partially rescues this phenotype. 5,[11][12][13][14] In this context, FLCN is not unlike the 6 additional genes that have so far been implicated in kidney cancer (VHL, MET, TSC1, TSC2, FH, and SDH), in that they all interact with metabolic pathways that respond to stress or nutrient stimulation (reviewed by Linehan et al 15 ). However, mounting evidence indicates that folliculin may also reg...

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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

Cited by 51 publications

References 28 publications

Novel intronic germline FLCN gene mutation in a patient with multiple ipsilateral renal neoplasms

Novel intronic germline FLCN gene mutation in a patient with multiple ipsilateral renal neoplasms

Jak/Stat signalling in niche support cells regulatesdpptranscription to control germline stem cell maintenance in theDrosophilaovary

The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dubé syndrome is required for murine B-cell development

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