Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway

Piao, Xianghua; Kobayashi, Toshiyuki; Wang, Lu; Shiono, Masatoshi; Takagi, Yumiko; Sun, Guodong; Abe, Masaaki; Hagiwara, Yoshihiro; Zhang, Danqing; Okimoto, Kazuo; Kouchi, Mami; Matsumoto, Izumi; Hino, Okio

doi:10.1016/j.bbrc.2009.08.070

Cited by 24 publications

(24 citation statements)

References 16 publications

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“…Multiple phosphorylations in FLCN are caused by downregulation of tuberin. 21 The mammalian target of rapamycin kinase (mTOR) with these 2 complexes mTORC1 and mTORC2 is involved in many cellular activities. Recent findings suggest that FLCN is involved in mTORC1-related pathways.…”

Section: Discussionmentioning

confidence: 99%

Syndrome of Birt–Hogg–Dubé, a Histopathological Pitfall With Similarities to Tuberous Sclerosis

Spring

Fellmann²,

Giraud³

et al. 2013

The American Journal of Dermatopathology

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Birt-Hogg-Dubé Syndrome (BHD) is a rare condition, transmitted as an autosomal-dominant trait. The etiology is due to a mutation in the BHD gene, which encodes folliculin (FLCN), located on chromosome 17p. The skin changes observed are benign skin tumors consisting of hamartomas of the hair follicle with dermal changes. Patients with BHD have an increased risk of spontaneous pneumothorax due to rupture of lung cysts and an increased risk of kidney tumors. We report 3 new cases of BHD and discuss their clinical features, histopathological findings, and molecular diagnostics. We highlight the importance of genetic analysis to confirm the diagnosis because of the clinical pitfalls involved in establishing a diagnosis. Finally, we discuss the histopathological features in BHD and tuberous sclerosis complex and focus on their overlapping criterias. A correct diagnosis is essential as it can be life saving for patients.

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Section: Discussionmentioning

confidence: 99%

Syndrome of Birt–Hogg–Dubé, a Histopathological Pitfall With Similarities to Tuberous Sclerosis

Spring

Fellmann²,

Giraud³

et al. 2013

The American Journal of Dermatopathology

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“…siRNA for tuberous sclerosis complex 2 (TSC2) and Raptor were purchased from TAKARA (Shiga, Japan). The nucleotide sequences are: siTSC2, 5′-GGCCCUCACAGACAAUGGA-3′; and siRaptor, 5′-GCCUGAGUCUGUGAAUGUA-3′ [25]. 5′-GCUGCAAUCGAUUGAUAGC-3′ was used as a control siRNA.…”

Section: Methodsmentioning

confidence: 99%

Dual Regulation of Cadmium-Induced Apoptosis by mTORC1 through Selective Induction of IRE1 Branches in Unfolded Protein Response

2013

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Cadmium (Cd) causes generation of reactive oxygen species (ROS) that trigger renal tubular injury. We found that rapamycin, an inhibitor of mTORC1, attenuated Cd-induced apoptosis in renal tubular cells. Knockdown of Raptor, a positive regulator of mTORC1, also had the similar effect. However, rapamycin did not alter generation of ROS, suggesting that mTORC1 is a target downstream of ROS. Indeed, ROS caused activation of mTORC1, which contributed to induction of a selective branch of the unfolded protein response (UPR); i.e., the IRE1 pathway. Although Cd triggered three major UPR pathways, activation of mTORC1 by Cd did not contribute to induction of the PERK–eIF2α and ATF6 pathways. Consistently, knockdown of Raptor caused suppression of JNK without affecting the PERK–eIF2α pathway in Cd-exposed cells. Knockdown of TSC2, a negative regulator of mTORC1, caused activation of mTORC1 and enhanced Cd induction of the IRE1–JNK pathway and apoptosis without affecting other UPR branches. Inhibition of IRE1α kinase led to suppression of JNK activity and apoptosis in Cd-treated cells. Dominant-negative inhibition of JNK also suppressed Cd-induced apoptosis. In contrast, inhibition of IRE1α endoribonuclease activity or downstream XBP1 modestly enhanced Cd-induced apoptosis. In vivo, administration with rapamycin suppressed activation of mTORC1 and JNK, but not eIF2α, in the kidney of Cd-treated mice. It was correlated with attenuation of tubular injury and apoptotic cell death in the tubules. These results elucidate dual regulation of Cd-induced renal injury by mTORC1 through selective induction of IRE1 signaling.

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“…FLCN has been linked to the AMPK signaling pathway, as FLCN binds to AMPK through FNIP (5,11,12). The FLCN-AMPK interaction is controlled by the phosphorylation of FLCN on 2 sites (serine 62 and 302), suggesting possible regulatory roles in AMPKdependent energy sensing and maintenance of energy homeosta- sis (31,32). Through allosteric interactions with AMP and ADP, AMPK acutely monitors adenylate charge fluctuations.…”

Section: Increased Pgc-1α Expression In Flcn-null Cells Enhances Ros mentioning

confidence: 99%

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

et al. 2014

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The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPKdependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.

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Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway

Cited by 24 publications

References 16 publications

Syndrome of Birt–Hogg–Dubé, a Histopathological Pitfall With Similarities to Tuberous Sclerosis

Syndrome of Birt–Hogg–Dubé, a Histopathological Pitfall With Similarities to Tuberous Sclerosis

Dual Regulation of Cadmium-Induced Apoptosis by mTORC1 through Selective Induction of IRE1 Branches in Unfolded Protein Response

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation

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