Schlisio, S. et al. The kinesin KIF1B acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 22, 884-893.This paper showed that KIF1B is necessary and sufficient for PHD3-induced apoptosis

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Genes & Development (Impact Factor: 10.8). 05/2008; 22(7):884-93. DOI: 10.1101/gad.1648608
Source: PubMed


VHL, NF-1, c-Ret, and Succinate Dehydrogenase Subunits B and D act on a developmental apoptotic pathway that is activated when nerve growth factor (NGF) becomes limiting for neuronal progenitor cells and requires the EglN3 prolyl hydroxylase as a downstream effector. Germline mutations of these genes cause familial pheochromocytoma and other neural crest-derived tumors. Using an unbiased shRNA screen we found that the kinesin KIF1Bbeta acts downstream from EglN3 and is both necessary and sufficient for neuronal apoptosis when NGF becomes limiting. KIF1Bbeta maps to chromosome 1p36.2, which is frequently deleted in neural crest-derived tumors including neuroblastomas. We identified inherited loss-of-function KIF1Bbeta missense mutations in neuroblastomas and pheochromocytomas and an acquired loss-of-function mutation in a medulloblastoma, arguing that KIF1Bbeta is a pathogenic target of these deletions.

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    • "Germline mutations in several of these susceptibility genes cause adrenomedullary tumor syndromes in which the patient presents with PCCs in addition to various syndromic manifestations (Favier et al., 2015), NF1 mutations cause neurofibromatosis type 1 in which 5% of patients can develop PCCs, RET mutations cause multiple endocrine neoplasia type 2, VHL mutations cause the von Hippel–Lindau syndrome, mutations in diverse SDHx genes have been linked to different hereditary paraganglioma and/or PCC syndromes named PGL1-4, mutations in EPAS1/HIF2A have been associated with the polycythemia-paraganglioma syndrome (Zhuang et al., 2012) and the Reed syndrome gene FH was recently found mutated in PCCs (Castro-Vega et al., 2014). Gene expression analyses have revealed that the PCCs can be clustered into mainly two different subgroups relating to genetic events and their aberrant pathways: VHL/ SDHx/EPAS1-mutated tumors associate to stabilization of hypoxia inducible factors while KIF1Bb/ MAX/NF1/RET/TMEM127-mutated tumors correlate to the activation of kinase signalling pathways (Eisenhofer et al., 2004; Schlisio et al., 2008; Dahia, 2014; Welander et al., 2014a; Favier et al., 2015). The genetics underlying sporadic PCCs are not yet clearly understood, and a majority of the tumors still lack a defined genetic driver event (Welander et al., 2011; Favier et al., 2015). "
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    ABSTRACT: As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    No preview · Article · May 2015 · Genes Chromosomes and Cancer
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    • "However, no specific tumor suppressor gene at 1p36 has yet been identified. Previous studies have identified CHD5 [9] and KIF1B [10] as candidate tumor suppressor genes in this region, and more recently it was reported that disruption of PER3 function may indicate the likelihood of tumor recurrence in patients with ERα-positive tumors [11]. However, to date, no specific roles for these genes in breast cancer development have been demonstrated. "
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    ABSTRACT: Background CDK11p58, a Ser/Thr kinase that belongs to the cell division cycle 2-like 1 (CDC2L1) subfamily, is associated with cell cycle progression, tumorigenesis and apoptotic signaling. CDK11p58 is also involved in the regulation of steroid receptors, such as androgen and estrogen receptors. We previously found that CDK11p58 was abnormally expressed in prostate cancer. However, its role in breast cancer remains unclear. Methods CDK11p58 expression was evaluated by immunohistochemical staining in a tissue array. A Transwell assay was used to detect invasion and metastasis in breast cancer cells. The TaqMan® Metastasis Gene Expression Assay was used to search for potential downstream factors in the CDK11p58 signaling pathway. qRT-PCR was used to evaluate mRNA levels, and the dual luciferase array was used to analyze promoter activity. Western blotting was used to detect the protein level. Results CDK11p58 expression was negatively correlated with node status (P = 0.012), relapse status (P = 0.002) and metastasis status (P = 0.023). Kaplan-Meier survival curves indicated that the disease-free survival (DFS) was significantly poor in breast cancer patients with low CDK11 expression. Interestingly, using the breast cancer cell lines ZR-75-30 and MDA-MB-231, we found that CDK11p58 was capable of repressing the migration and invasion of ERα-positive breast cancer cells, but not ERα-negative breast cancer cells, in a kinase-dependent manner. Gene expression assays demonstrated that integrin β3 mRNA was dramatically repressed by CDK11p58, and luciferase results confirmed that the integrin β3 promoter was inhibited by CDK11p58 through ERα repression. The expression of integrin β3 was highly related to ERα signaling; ERα overexpression stimulated integrin β3 expression, whereas siRNA-mediated knockdown of ERα attenuated integrin β3 expression. Conclusions These data indicate that CDK11p58 is an anti-metastatic gene in ERα-positive breast cancer and that the regulation of integrin β3 by CDK11p58 via the repression of ERα signaling may constitute part of a signaling pathway underlying breast cancer invasion.
    Full-text · Article · Aug 2014 · BMC Cancer
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    • "Amongst these, the most relevant are those of the mitochondrial succinate dehydrogenase (SDH) complex subunits genes (SDHA, SDHB, SDHC, and SDHD) and one complex cofactor, SDHAF2, mainly involved in head and neck and abdominal paragangliomas and initially discovered by Baysal et al. [30] [31] [32] [33] [34]. More recently, the TMEM127, MAX, HIF2A, EGLN1, KIF1B, and H-RAS complete the list of susceptibility genes implicated in the development of paragangliomas/pheochromocytomas [35] [36] [37] [38] [39] [40]. So far, H-RAS mutations have been identified only at a somatic level. "
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    ABSTRACT: Paragangliomas are rare neuroendocrine tumors that arise in the sympathetic or parasympathetic nervous system. Sympathetic paragangliomas are mainly found in the adrenal medulla (designated pheochromocytomas) but may also have a thoracic, abdominal, or pelvic localization. Parasympathetic paragangliomas are generally located at the head or neck. Knowledge concerning the familial forms of paragangliomas has greatly improved in recent years. Additionally to the genes involved in the classical syndromic forms: VHL gene (von Hippel-Lindau), RET gene (Multiple Endocrine Neoplasia type 2), and NF1 gene (Neurofibromatosis type 1), 10 novel genes have so far been implicated in the occurrence of paragangliomas/pheochromocytomas: SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAX, EGLN1, HIF2A, and KIF1B. It is currently accepted that about 35% of the paragangliomas cases are due to germline mutations in one of these genes. Furthermore, somatic mutations of RET, VHL, NF1, MAX, HIF2A, and H-RAS can also be detected. The identification of the mutation responsible for the paraganglioma/pheochromocytoma phenotype in a patient may be crucial in determining the treatment and allowing specific follow-up guidelines, ultimately leading to a better prognosis. Herein, we summarize the most relevant aspects regarding the genetics and clinical aspects of the syndromic and nonsyndromic forms of pheochromocytoma/paraganglioma aiming to provide an algorithm for genetic testing.
    Full-text · Article · May 2014 · International Journal of Endocrinology
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