Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway

Pollard, Patrick J.; Spencer‐Dene, Bradley; Shukla, Deepa; Howarth, Kimberley; Nye, Emma; El‐Bahrawy, Mona; Deheragoda, Maesha; Joannou, Maria; McDonald, Stuart; Martin, Alison; Igarashi, Peter; Varsani-Brown, Sunita; Rosewell, Ian; Poulsom, Richard; Maxwell, Patrick H.; Stamp, Gordon; Tomlinson, Ian

doi:10.1016/j.ccr.2007.02.005

Cited by 162 publications

(179 citation statements)

References 43 publications

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“…Upregulation of glycolysis is a logical consequence of downregulation of the oxidative ATP production pathway due to the lack of the activity of a key metabolic enzyme FH. FH-deficient leiomyomas have also been shown to activate hypoxia response through HIF1-a pathway induction (Eng et al, 2003;Pollard et al, 2003Pollard et al, , 2005aPollard et al, , b, 2007Isaacs et al, 2005). The transcripts associated with hypoxia response were, however, only induced in FH-deficient leiomyomas, but not in sporadic leiomyomas or fibroblasts with FH deficiency or MELAS (Vanharanta et al, 2006).…”

Section: Srf-fos-junb Pathway In Myomas N Raimundo Et Almentioning

confidence: 85%

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

et al. 2009

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Defects of metabolic enzymes result in a variety of manifestations not logically explained by the primary metabolic function. Dominant defects of fumarate hydratase (FH) result in predisposition to cutaneous and uterine leiomyomas, and renal cell cancer. FH is a metabolic enzyme of the tricarboxylic acid cycle, and its tumorsuppressor mechanism is not fully understood. We compared the consequences of FH deficiency and respiratory chain (RC) deficiency using global expression pattern of diploid primary fibroblasts. This approach utilized the information that RC defects do not seem to predispose to tumorigenesis, and the aim was to identify FH-specific signaling effects that might have relevance to tumor formation. These results were then compared to global expression patterns of FH-deficient and sporadic uterine leiomyoma data sets. We show here that FH-deficient fibroblasts share a common transcriptional fingerprint with FH-deficient and sporadic leiomyomas, highlighting the downregulation of serum response factor (SRF)-regulated transcripts, particularly the FOS-JUNB pathway. We confirmed the downregulation of this pathway at transcriptional and protein level. SRF has a fundamental function in the differentiation of smooth muscle progenitor cells, and its downregulation both in diploid FH-deficient primary fibroblasts and in leiomyomas suggests an early function in the mechanism of uterine leiomyoma formation in FH deficiency. Concordantly, the phosphorylated form of SRF, known to activate transcription, is undetectable in leiomyomas whereas clearly detected in several nuclei in the differentiated myometrium. A similar transcriptional SRFpathway fingerprint in FH-deficient and sporadic leiomyomas emphasizes the potential importance of this pathway in primary events leading to leiomyomatosis.

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Section: Srf-fos-junb Pathway In Myomas N Raimundo Et Almentioning

confidence: 85%

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

et al. 2009

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“…Renal cyst development in PEPCK-Cre mutant was dependent on intact HIF signaling, but not on HIF-1a, as cysts were not observed in VHL/ARNT double knockout mice and HIF-1a was not required for cyst formation. 83 Activation of HIF signaling has also been suggested to promote renal cystogenesis in a mouse model of fumarate hydratase deficiency, which leads to HIF prolyl-hydroxylase inhibition and HIF-a stabilization, 127 indicating that HIF-mediated renal cystogenesis is not dependent on VHL status. In contrast to pVHL inactivation with PEPCK-Cre transgenics, inactivation of pVHL using THP-Cre, which targets the medullary thick ascending loop of Henle (mTAL) and the early distal tubule, did not produce renal cysts.…”

Section: Pvhl and Renal Cell Cancermentioning

confidence: 99%

The VHL tumor suppressor and HIF: insights from genetic studies in mice

2008

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The von Hippel-Lindau tumor suppressor gene product, pVHL, functions as the substrate recognition component of an E3-ubiquitin ligase, which targets the oxygen-sensitive a-subunit of hypoxia-inducible factor (HIF) for rapid proteasomal degradation under normoxic conditions and as such plays a central role in molecular oxygen sensing. Mutations in pVHL can be found in familial and sporadic clear cell carcinomas of the kidney, hemangioblastomas of the retina and central nervous system, and pheochromocytomas, underscoring its gatekeeper function in the pathogenesis of these tumors. Tissue-specific gene targeting of VHL in mice has demonstrated that efficient execution of pVHL-mediated HIF proteolysis under normoxia is fundamentally important for survival, proliferation, differentiation and normal physiology of many cell types, and has provided novel insights into the biological function of individual HIF transcription factors. In this review, we discuss the role of HIF in the development of the VHL phenotype. Germ-line mutations in the von Hippel-Lindau tumor (VHL) suppressor can be found in patients with VHL disease, a rare familial tumor syndrome characterized by the development of highly vascularized tumors in multiple organs. Major clinical manifestations of VHL disease include hemangioblastomas of the retina and central nervous system (CNS), renal cysts and renal cell carcinoma of the clear cell type (CC-RCC), pancreatic cysts and tumors, as well as pheochromocytomas. 1 The VHL tumor suppressor is also mutated in the majority of sporadic CC-RCCs, 2 highlighting its critical and central role in the regulation of cell growth and differentiation of epithelial kidney cells. Although the molecular function of the VHL gene product, pVHL, was initially not known when it was first identified by positional cloning in 1993, 3 observations that oxygen-dependent regulation of hypoxia-inducible genes was lost in VHL-deficient cell lines suggested a role for pVHL in oxygen sensing. [4][5][6] In a seminal paper, Maxwell et al. 7 showed that pVHL was critical for targeting the a-subunit of hypoxia-inducible factor (HIF) for oxygen-dependent proteolysis, thus providing a direct molecular link between VHLassociated tumorigenesis and oxygen sensing via HIF. HIFs belong to the PAS (Per-arylhydrocarbon receptor nuclear translocator (ARNT)-Sim) family of basic helix-loop-helix (bHLH) transcription factors and bind DNA as heterodimers. They consist of an oxygen-sensitive a-subunit and a constitutively expressed b-subunit, also known as ARNT or HIF-b. pVHL associates with the elongins B and C, cullin2 and Rbx [8][9][10][11][12] and functions as the substrate recognition component of an E3-ubiquitin ligase that ubiquitylates HIF-a. [13][14][15][16][17][18][19] All three HIF a-subunits, HIF-1a, HIF-2a and HIF-3a interact with pVHL. 7,20 This pVHL-HIF-a interaction is highly conserved between species, requires iron-and oxygen-dependent hydroxylation of specific proline residues (Pro402 and Pro564 in human HIF-1a; Pro405 and Pro531 in ...

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“…T6793). Immunohistochemistry using anti-HIF1a (Novus Biologicals; NB100-105) and anti-HIF2a (Pollard et al, 2007; PM8) antibodies was performed using the DakoCytomation Catalyzed Signal Amplification System. Collecting ducts were labelled by incubating kidney sections with FITC-tagged D. biflorus agglutinin (20 mg/ml; Vector Laboratories).…”

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation

Frew

Thoma

Georgiev

et al. 2008

EMBO J

141

148

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In patients with von Hippel-Lindau (VHL) disease, renal cysts and clear cell renal cell carcinoma (ccRCC) arise from renal tubular epithelial cells containing biallelic inactivation of the VHL tumour suppressor gene. However, it is presumed that formation of renal cysts and their conversion to ccRCC involve additional genetic changes at other loci. Here, we show that cystic lesions in the kidneys of patients with VHL disease also demonstrate activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Strikingly, combined conditional inactivation of Vhlh and the Pten tumour suppressor gene, which normally antagonises PI3K signalling, in the mouse kidney, elicits cyst formation after short latency, whereas inactivation of either tumour suppressor gene alone failed to produce such a phenotype. Interestingly, cells lining these cysts frequently lack a primary cilium, a microtubule-based cellular antenna important for suppression of uncontrolled kidney epithelial cell proliferation and cyst formation. Our results support a model in which the PTEN tumour suppressor protein cooperates with pVHL to suppress cyst development in the kidney.

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Targeted Inactivation of Fh1 Causes Proliferative Renal Cyst Development and Activation of the Hypoxia Pathway

Cited by 162 publications

References 43 publications

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

Downregulation of SRF–FOS–JUNB pathway in fumarate hydratase deficiency and in uterine leiomyomas

The VHL tumor suppressor and HIF: insights from genetic studies in mice

pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation

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