Novel Homozygous Mutation of the Internal Translation Initiation Start Site ofVHLis Exclusively Associated with Erythrocytosis: Indications for Distinct Functional Roles of von Hippel-Lindau Tumor Suppressor Isoforms

2015 ◽  
Vol 36 (11) ◽  
pp. 1039-1042 ◽  
Author(s):  
Marije Bartels ◽  
Marieke M. van der Zalm ◽  
Brigitte A. van Oirschot ◽  
Frank S. Lee ◽  
Rachel H. Giles ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Translation Initiation ◽  
Homozygous Mutation ◽  
Start Site ◽  
Functional Roles ◽  
Von Hippel Lindau ◽  
Internal Translation ◽  
Translation Initiation Start

scholarly journals Alternative translation initiation generates a functionally distinct isoform of the stress-activated kinase MK2

2018 ◽  
Author(s):  
Philipp Trulley ◽  
Goda Snieckute ◽  
Dorte Bekker-Jensen ◽  
Manoj B. Menon ◽  
Robert Freund ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Translation Initiation ◽  
Specific Binding ◽  
Protein Isoforms ◽  
Early Gene ◽  
Start Codon ◽  
Start Site ◽  
Alternative Translation ◽  
Transcriptional Gene Regulation ◽  
Translation Initiation Start

AbstractShaping of the proteome by alternative translation is an important mechanism of post-transcriptional gene regulation. It can lead to the expression of multiple protein isoforms originating from the same mRNA. Here we show that a novel, abundant and long isoform of the stress/p38MAPK-activated kinase MK2, a key regulator of transcription, migration, death signaling and post-transcriptional gene regulation, is constitutively translated from an alternative CUG translation initiation start site located in the 5′UTR of its mRNA. GC-rich sequences and putative G-quadruplex structures influence the usage of that codon as a translation initiation start site and the RNA helicase eIF4A1 is needed to ensure alternative isoform translation. We recapitulated the usage of the alternative start codon and determined the molecular properties of the short and a long MK2 isoforms. Phenotypically, only the short isoform phosphorylated Hsp27, supported migration and stress-induced immediate early gene (IEG) expression. Interaction profiling by quantitative mass-spectrometry revealed short isoform-specific binding partners that were associated with migration. In contrast, the long isoform contains additional putative phosphorylation sites in its unique N-terminus. In sum, our data reveal a longer and previously non-described isoform of MK2 with distinct physiological properties originating from alternative translation.

scholarly journals Hydrogen Sulfide Increases Hypoxia-inducible Factor-1 Activity Independently of von Hippel–Lindau Tumor Suppressor-1 inC. elegans

2010 ◽  
Vol 21 (1) ◽  
pp. 212-217 ◽  
Author(s):  
Mark W. Budde ◽  
Mark B. Roth
Keyword(s):  
Hydrogen Sulfide ◽  
Tumor Suppressor ◽  
Environmental Changes ◽  
Hypoxia Inducible Factor ◽  
Low Oxygen ◽  
Animal Cells ◽  
Von Hippel Lindau ◽  
C Elegans ◽  
Reporter Activity ◽  
And Behavior

Rapid alteration of gene expression in response to environmental changes is essential for normal development and behavior. The transcription factor hypoxia-inducible factor (HIF)-1 is well known to respond to alterations in oxygen availability. In nature, low oxygen environments are often found to contain high levels of hydrogen sulfide (H2S). Here, we show that Caenorhabditis elegans can have mutually exclusive responses to H2S and hypoxia, both involving HIF-1. Specifically, H2S results in HIF-1 activity throughout the hypodermis, whereas hypoxia causes HIF-1 activity in the gut as judged by a reporter for HIF-1 activity. C. elegans require hif-1 to survive in room air containing trace amounts of H2S. Exposure to H2S results in HIF-1 nuclear localization and transcription of HIF-1 targets. The effects of H2S on HIF-1 reporter activity are independent of von Hippel–Lindau tumor suppressor (VHL)-1, whereas VHL-1 is required for hypoxic regulation of HIF-1 reporter activity. Because H2S is naturally produced by animal cells, our results suggest that endogenous H2S may influence HIF-1 activity.

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