In vitro
 and 
 In vivo
 Models Analyzing von Hippel-Lindau Disease-Specific Mutations

Rathmell, W. Kimryn; Hickey, Michele M.; Bezman, Natalie; Chmielecki, C.; Carraway, Natalie C.; Simon, M. Celeste

doi:10.1158/0008-5472.can-04-1430

Cited by 58 publications

(59 citation statements)

References 42 publications

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“…These findings were surprising, but are in concordance with observations made by Carmeliet et al 129 who showed that HIF-1a-deficient teratocarcinomas had a growth advantage compared to wild type. However, growth suppression in VHLÀ/À teratocarcinomas may not be entirely dependent on HIF-1, as introduction of a mutated pVHL species (Y112H) into the VHLÀ/À background remained growth suppressive despite restoration of HIF-a regulation, 130 suggesting HIF-independent functions of pVHL in this model.…”

Section: Vhl Phenotypes In Non-renal Tissues: Is It All Hif?mentioning

confidence: 83%

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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Section: Vhl Phenotypes In Non-renal Tissues: Is It All Hif?mentioning

confidence: 83%

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

2008

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“…52 Introduction of pVHL mutations (Y98N, Y112N, W117R, and R167Q) that are associated with a high risk of renal carcinoma (type 2B) into VHL-deficient cell lines leads to increased normoxic HIF-1a and HIF-2a stabilization compared to wildtype VHL. 57,58 Cells harboring these mutations also display increased proliferation in serum-depleted media and growth in orthotopic xenograft assays, which can be reversed by shRNA-mediated knock down of HIF-2a. 57 The R167Q mutation, in particular, uniquely disrupts regulation of HIF-2a in ES cells.…”

Section: Role In Tumorigenesismentioning

confidence: 99%

“…57 The R167Q mutation, in particular, uniquely disrupts regulation of HIF-2a in ES cells. 58 In contrast, type 2A mutations (Y98H, Y112H, A149T, and T157I), which have a lower risk for renal tumors, display reduced levels of normoxic HIF-a accumulation and growth in xenograft assays compared to type 2B mutants. 57 In contrast to tumor-associated VHL mutations, the R200W mutation in pVHL leads to Chuvash polycythemia, a heritable disease characterized by elevated levels of serum Epo and VEGF.…”

Section: Role In Tumorigenesismentioning

confidence: 99%

Biology of hypoxia-inducible factor-2α in development and disease

Patel¹,

Simon²

2008

Cell Death Differ

295

237

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The transcriptional response to hypoxia is primarily mediated by two hypoxia-inducible factors -HIF-1a and HIF-2a. While these proteins are highly homologous, increasing evidence suggests they have unique transcriptional targets and differential impact on tumor growth. Furthermore, non-transcriptional effects of the HIF-a subunits, including effects on the Notch and c-Myc pathways, contribute to their distinct functions. HIF-2a transcriptional targets include genes involved in erythropoiesis, angiogenesis, metastasis, and proliferation. Therefore, HIF-2a contributes significantly to both normal physiology as well as tumorigenesis. Here, we summarize the function of HIF-2a during development as well as its contribution to pathologic conditions, such as tumors and vascular disease. Cell Death and Differentiation (2008) Cells, tissues, and organisms experience reduced oxygen (O 2 ) tension, or 'hypoxia,' under both physiologic and pathologic conditions. 1 During the rapid cell proliferation associated with early embryonic development, physiologic hypoxia stimulates the development of the hematopoietic and circulatory systems. 2 Rapidly growing tumors also experience hypoxia due to insufficient and defective vascularization. 3 The hypoxia-inducible factors (HIFs) mediate the adaptive response to decreased O 2 availability at the cellular and organismal level. HIFs are heterodimeric proteins belonging to the basic helix-loop-helix (bHLH)/Per-ARNTSim (PAS) domain family of transcription factors. 4 Under normoxic conditions, the HIF-a subunits are hydroxylated on key proline residues, which allows for recognition by the von Hippel-Lindau (pVHL) tumor suppressor, the substrate recognition component of an E3 ubiquitin ligase complex that targets HIF-a for proteosomal degradation. [5][6][7][8][9] In hypoxic conditions, these hydroxylation events are inhibited allowing the a subunits to enter the nucleus and bind the stable subunit or aryl hydrocarbon receptor nuclear translocator (ARNT), forming a functional transcriptional complex. Among HIF transcriptional targets are genes involved in glycolysis, angiogenesis, erythropoiesis, cell death, and differentiation. 10

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“…Control tissues included EBER-positive Hodgkin lymphoma for LMP1, and renal cell carcinoma tissue for HIF-1a and CD31. Additional controls were renal cell carcinoma cell line pellets (RCC4 2-1 over expresses HIF-1a while RCC4 3-14 does not) that were fixed in formalin and paraffin embedded [17]. Specificity was assured in all specimens by parallel stains omitting the primary antibody.…”

Section: Case Selectionmentioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein 1 is not Associated with Vessel Density nor with Hypoxia Inducible Factor 1 Alpha Expression in Nasopharyngeal Carcinoma Tissue

Benders

Tang²,

Middeldorp

et al. 2009

Head and Neck Pathol

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Hypoxia-inducible factor-1a (HIF-1a) and the neo-angiogenic factors induced as a result of hypoxiainducible factor transcriptional activation may contribute to tumorigenesis by inducing vessel formation that in turn provides oxygen and nutrients promoting tumor expansion. In vitro studies of nasopharyngeal carcinoma (NPC), an aggressive malignancy that is nearly always infected by Epstein-Barr virus, show HIF-1a is upregulated by viral latent membrane protein 1 (LMP1). The current study used immunohistochemistry to examine the extent to which HIF-1a and LMP1 are co-expressed in naturally infected NPC tissues. Analytic procedures were optimized for sensitive localization of HIF-1a and LMP1 in fixed tissue sections using immunohistochemistry with sensitive fluorescent and signal amplification technologies. Vessel density was quantified by CD31 immunohistochemistry. LMP1 was expressed focally in all 18 NPCs examined, including 7/8 in situ lesions. There was no consistent co-localization with HIF-1a which was usually only weakly expressed in a subset of neoplastic cells. Neither LMP1 nor HIF-1a expression correlated with vessel density, and degree of vascularization varied widely among cases. Advanced immunohistochemical technologies reveal that LMP1 is expressed more commonly than previously reported in NPC. There is no consistent relationship between LMP1 and either HIF-1a expression or degree of microvasculature. The biologic basis for the wide variation in vessel density deserves further investigation.

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In vitro and In vivo Models Analyzing von Hippel-Lindau Disease-Specific Mutations

Cited by 58 publications

References 42 publications

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

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

Biology of hypoxia-inducible factor-2α in development and disease

Epstein-Barr Virus Latent Membrane Protein 1 is not Associated with Vessel Density nor with Hypoxia Inducible Factor 1 Alpha Expression in Nasopharyngeal Carcinoma Tissue

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