Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

Logo MUG-Forschungsportal

Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Wiesner, T; Lee, W; Obenauf, AC; Ran, L; Murali, R; Zhang, QF; Wong, EW; Hu, W; Scott, SN; Shah, RH; Landa, I; Button, J; Lailler, N; Sboner, A; Gao, D; Murphy, DA; Cao, Z; Shukla, S; Hollmann, TJ; Wang, L; Borsu, L; Merghoub, T; Schwartz, GK; Postow, MA; Ariyan, CE; Fagin, JA; Zheng, D; Ladanyi, M; Busam, KJ; Berger, MF; Chen, Y; Chi, P.
Alternative transcription initiation leads to expression of a novel ALK isoform in cancer.
Nature. 2015; 526(7573):453-457 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Obenauf Anna Christina
Wiesner Thomas
Altmetrics:

Dimensions Citations:

Plum Analytics:
Number of Figures: 13
| | | | | | | | | | | | |
Abstract:
Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in ∼11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.
Find related publications in this database (using NLM MeSH Indexing)
Alleles -
Animals -
Cell Line, Tumor -
Cell Proliferation -
Cell Transformation, Neoplastic -
Female -
Gene Expression Regulation, Neoplastic - genetics
HEK293 Cells -
Histones - chemistry
Histones - metabolism
Humans -
Introns - genetics
Isoenzymes - antagonists & inhibitors
Isoenzymes - biosynthesis
Isoenzymes - chemistry
Isoenzymes - genetics
Lysine - metabolism
Methylation -
Mice -
Molecular Sequence Data -
Molecular Weight -
NIH 3T3 Cells -
Neoplasms - drug therapy
Neoplasms - enzymology
Neoplasms - genetics
Oncogenes - genetics
Protein Structure, Tertiary - genetics
RNA Polymerase II - metabolism
RNA, Messenger - analysis
RNA, Messenger - genetics
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Receptor Protein-Tyrosine Kinases - biosynthesis
Receptor Protein-Tyrosine Kinases - chemistry
Receptor Protein-Tyrosine Kinases - genetics
Signal Transduction -
Transcription Initiation, Genetic -

© Meduni Graz Impressum