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Anaplastic Lymphoma...
Anaplastic Lymphoma Kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells
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- Schönherr, Christina (author)
- Umeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)
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- Ruuth, Kristina (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Hallberg
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- Kamaraj, Sattu (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Hallberg
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- Wang, C. L. (author)
- College of Life Sciences and Biotechnology, Beijing Forestry University, Beijing, China
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- Yang, H. L. (author)
- College of Life Sciences and Biotechnology, Beijing Forestry University, Beijing, China
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- Combaret, V. (author)
- Centre Léon Bérard, FNCLCC, Laboratoire de Recherche Translationnelle, Lyon, France
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- Djos, Anna, 1983 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik,Institute of Biomedicine, Department of Medical and Clinical Genetics,Department of Clinical Genetics, University of Gothenburg, Gothenburg, Sweden
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- Martinsson, Tommy, 1956 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för biomedicin, avdelningen för medicinsk genetik och klinisk genetik,Institute of Biomedicine, Department of Medical and Clinical Genetics,Department of Clinical Genetics, University of Gothenburg, Gothenburg, Sweden
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- Christensen, J. G. (author)
- Global Research and Development, Department of Research Pharmacology, La Jolla Laboratories, La Jolla, CA, USA
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- Palmer, Ruth H (author)
- Umeå universitet,Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet),Palmer
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- Hallberg, Bengt (author)
- Umeå universitet,Institutionen för molekylärbiologi (Medicinska fakulteten),Hallberg
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(creator_code:org_t)
- 2012-01-30
- 2012
- English.
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In: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 31:50, s. 5193-5200
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Abstract
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- Neuroblastoma is a neural crest-derived embryonal tumour of the postganglionic sympathetic nervous system and a disease with several different chromosomal gains and losses, which include MYCN-amplified neuroblastoma on chromosome 2, deletions of parts of the chromosomes 1p and 11q, gain of parts of 17q and triploidy. Recently, activating mutations of the ALK (Anaplastic Lymphoma Kinase) RTK (Receptor Tyrosine Kinase) gene have been described in neuroblastoma. A meta-analysis of neuroblastoma cases revealed that ALK mutations (49 of 709 cases) in relation to genomic subtype were most frequently observed in MYCN amplified tumours (8.9%), correlating with a poor clinical outcome. MYCN proteins target proliferation and apoptotic pathways, and have an important role in the progression of neuroblastoma. Here, we show that both wild-type and gain-of-function mutants in ALK are able to stimulate transcription at the MYCN promoter and initiate mRNA transcription of the MYCN gene in both neuronal and neuroblastoma cell lines. Further, this stimulation of MYCN gene transcription and de novo MYCN protein expression is abrogated by specific ALK inhibitors, such as crizotinib (PF-2341066), NVP-TAE684, and by small interfering RNA to ALK resulting in a decrease in proliferation rate. Finally, co-transfection of ALK gain-of-function mutations together with MYCN leads to an increase in transformation potential. Taken together, our results indicate that ALK signalling regulates initiation of transcription of the MYCN gene providing a possible explanation for the poor clinical outcome observed when MYCN is amplified together with activated ALK.
Subject headings
- NATURVETENSKAP -- Biologi -- Genetik (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- neuroblastoma
- anaplastic lymphoma kinase
- ALK
- MYCN
- transcription factor
- n-myc
- tyrosine kinase
- lung-cancer
- activating mutations
- c-myc
- inhibitors
- expression
- protein
- crizotinib
- receptor
Publication and Content Type
- ref (subject category)
- art (subject category)
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Oncogene
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- By the author/editor
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Schönherr, Chris ...
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Ruuth, Kristina
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Kamaraj, Sattu
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Wang, C. L.
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Yang, H. L.
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Combaret, V.
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show more...
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Djos, Anna, 1983
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Martinsson, Tomm ...
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Christensen, J. ...
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Palmer, Ruth H
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Hallberg, Bengt
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MEDICAL AND HEAL ...
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Oncogene
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University of Gothenburg
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Umeå University