The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor

Schlisio, Susanne; Kenchappa, Rajappa S.; Vredeveld, Liesbeth C.W.; George, Rani E.; Stewart, Rodney A.; Greulich, Heidi; Shahriari, Kristina; Nguyen, Nguyen V.; Pigny, Pascal; Dahia, Patricia L.M.; Pomeroy, Scott L.; Maris, John M.; Look, A. Thomas; Meyerson, Matthew; Peeper, Daniel S.; Carter, Bruce D.; Kaelin, William G.

doi:10.1101/gad.1648608

Cited by 305 publications

(316 citation statements)

References 44 publications

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“…This therefore suggests an a-ketoglutarate-induced, caspase-independent mode of cell death, which is at least partly HIF1a independent. Supporting evidence for the presence of PHD-dependent, HIF-independent cell death mechanisms highlights PHD3 as having a proapoptotic effect under normoxia in a number of cell types Bishop et al, 2008;Schlisio et al, 2008). It is important to observe that knockdown of either PHD2 or 3 failed to ablate completely the hypoxia-specific cell death response.…”

Section: Discussionmentioning

confidence: 99%

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

et al. 2009

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Cells exposed to low-oxygen conditions (hypoxia) alter their metabolism to survive. This response, although vital during development and high-altitude survival, is now known to be a major factor in the selection of cells with a transformed metabolic phenotype during tumorigenesis. It is thought that hypoxia-selected cells have increased invasive capacity and resistance to both chemo-and radiotherapies, and therefore represent an attractive target for antitumor therapy. Hypoxia inducible factors (HIFs) are responsible for the majority of gene expression changes under hypoxia, and are themselves controlled by the oxygen-sensing HIF prolyl hydroxylases (PHDs). It was previously shown that mutations in succinate dehydrogenase lead to the inactivation PHDs under normoxic conditions, which can be overcome by treatment with a-ketoglutarate derivatives. Given that solid tumors contain large regions of hypoxia, the reactivation of PHDs in these conditions could induce metabolic catastrophe and therefore prove an effective antitumor therapy. In this report we demonstrate that derivatized a-ketoglutarate can be used as a strategy for maintaining PHD activity under hypoxia. By increasing intracellular a-ketoglutarate and activating PHDs we trigger PHD-dependent reversal of HIF1 activation, and PHD-dependent hypoxic cell death. We also show that derivatized a-ketoglutarate can permeate multiple layers of cells, reducing HIF1a levels and its target genes in vivo.

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Section: Discussionmentioning

confidence: 99%

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

et al. 2009

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“…The vast majority of these patients belong to one of the following syndromes: von Hippel-Lindau (VHL) [5], multiple endocrine neoplasia type 2 (MEN 2) [6], von Recklinghausen (NF1) [7] or pheochromocytomaparaganglioma syndrome (PGL types 1-4) [8][9][10][11], which are caused by germline mutations in VHL, RET, NF1 and SDHx (SDHA, SDHB, SDHC, SDHD, and SDHAF2/SDH5), respectively. In addition, germline mutations in KIF1Bβ have been found in patients with PCCs, neuroblastomas and other neural and non-neural tumors [12,13]. More recently, EPAS1/HIF2A germline mutations were found in patients with PCCs/PGLs and polycythemia (polycythemia-paraganglioma syndrome) [14] Susceptibility genes for which no syndromic form has been described yet include EGLN1 [15], TMEM127 [16] and MAX [17].…”

Section: Introductionmentioning

confidence: 99%

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

et al. 2013

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Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel Lindau (VHL) syndrome. In VHL, only about 30% of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought for. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found in both patients with PCCs and PGLs. Since loss of 11q is a common event in VHLassociated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In this study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation as well as mRNA expression of SDHAF2 and SDHD was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. LOH was found in more than 50% of the VHL-associated PCCs, and was correlated to a significant decrease (p<0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression.In addition, the lack of mutations and promoter methylation in the investigated samples indicate that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.3

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“…For example, alterations of KIF3, 13 KIF1B, 14 KIF14, 15 and Kid 16 proteins were observed in breast cancer; KIF14 17 and KIF4A 18 were altered in lung cancer; and KIF1B was down-regulated in neurofibroma. 19 In addition, altered expression of EG5, 20 CENP-E, 21 KIF5B, 22 and KIF18A 23 proteins was associated with the development of different human cancers. Thus, an analysis of their expression may serve as useful tools for the early detection of tumorigenesis and for better predictions of prognosis for patients with cancer.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

“…Summarizing from previous studies, the expression of KIFs is regulated by the upstream transcription factor. For example, KIF1Bb is regulated by egl9 homolog 3 (EglN3), 19 MKLP1 is regulated by cut-like homeobox 1 (CUX1) and E2F transcription factor 1 (E2F1), 95 MKLP2 is regulated by forkhead box M1 (FoxM1), 61 and MCAK is regulated by Sp transcription factor 1 (Sp1) and E2F1. 96 The phosphorylation of KIFs reduced their binding to microtubules 97,98 and changed the localization and microtubule depolymerizing activity of KIF.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

“…4 To date, many studies have demonstrated that altered expression of kinesins is associated with the development and progression of various human cancers. [13][14][15][16][17][18][19][20][21][22][23] Abnormal kinesin expression alters the equal distribution of genetic materials during cell mitosis because of chromosome hypercondensation, aberrant spindle formation, anaphase bridges, defective cytokinesis, aneuploidy, Figure 1. The structure and functional domains of kinesin family proteins (KIFs) are illustrated.…”

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The role of kinesin family proteins in tumorigenesis and progression

Feng

2010

Cancer

110

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The kinesin superfamily contains a conserved class of microtubule-dependent molecular motor proteins that possess an adenosine triphosphatase activity and motion characteristics. The active movement of kinesins supports several cellular functions, including mitosis, meiosis, and the transport of macromolecules. Mitosis is a process of eukaryotic cell division that involves the division of nuclei, cytoplasm, organelles, and the cell membrane into 2 daughter cells with roughly equivalent portions of these cellular components. Any errors in this process could result in cell death, abnormality (such as gene deletion, chromosome translocation, or duplication), and cancer. Because mitosis is complex and highly regulated, alteration of kinesin expression or function could lead to carcinogenesis. Moreover, because human cancer is a gene-related disease involving abnormal cell growth, targeting kinesins may create a novel strategy for the control of human cancer. Indeed, several such drugs are being tested successfully in the clinic. In this review, the authors discuss in detail the structure and function of kinesins, the correlation of kinesin expression with tumorigenesis and progression, and the development of biomarkers and cancer-targeted therapy involving the kinesin family proteins. Cancer 2010;116:5150-60.

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The kinesin KIF1Bβ acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor

Cited by 305 publications

References 44 publications

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death

Role of SDHAF2 and SDHD in von Hippel–Lindau Associated Pheochromocytomas

The role of kinesin family proteins in tumorigenesis and progression

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