PMID- 36097292
OWN - NLM
STAT- MEDLINE
DCOM- 20220928
LR  - 20221119
IS  - 1545-9985 (Electronic)
IS  - 1545-9993 (Print)
IS  - 1545-9985 (Linking)
VI  - 29
IP  - 9
DP  - 2022 Sep
TI  - Isoform-resolved mRNA profiling of ribosome load defines interplay of HIF and 
      mTOR dysregulation in kidney cancer.
PG  - 871-880
LID - 10.1038/s41594-022-00819-2 [doi]
AB  - Hypoxia inducible factor (HIF) and mammalian target of rapamycin (mTOR) pathways 
      orchestrate responses to oxygen and nutrient availability. These pathways are 
      frequently dysregulated in cancer, but their interplay is poorly understood, in 
      part because of difficulties in simultaneous measurement of global and 
      mRNA-specific translation. Here, we describe a workflow for measurement of 
      ribosome load of mRNAs resolved by their transcription start sites (TSSs). Its 
      application to kidney cancer cells reveals extensive translational reprogramming 
      by mTOR, strongly affecting many metabolic enzymes and pathways. By contrast, 
      global effects of HIF on translation are limited, and we do not observe reported 
      translational activation by HIF2A. In contrast, HIF-dependent alterations in TSS 
      usage are associated with robust changes in translational efficiency in a subset 
      of genes. Analyses of the interplay of HIF and mTOR reveal that specific classes 
      of HIF1A and HIF2A transcriptional target gene manifest different sensitivity to 
      mTOR, in a manner that supports combined use of HIF2A and mTOR inhibitors in 
      treatment of kidney cancer.
CI  - (c) 2022. The Author(s).
FAU - Sugimoto, Yoichiro
AU  - Sugimoto Y
AD  - The Francis Crick Institute, London, UK.
FAU - Ratcliffe, Peter J
AU  - Ratcliffe PJ
AUID- ORCID: 0000-0002-2853-806X
AD  - The Francis Crick Institute, London, UK. peter.ratcliffe@crick.ac.uk.
AD  - Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, 
      University of Oxford, Oxford, UK. peter.ratcliffe@crick.ac.uk.
LA  - eng
GR  - CC2092/CRUK_/Cancer Research UK/United Kingdom
GR  - CC2092/MRC_/Medical Research Council/United Kingdom
GR  - CC2092/WT_/Wellcome Trust/United Kingdom
GR  - 106241/Z/14/Z/WT_/Wellcome Trust/United Kingdom
GR  - WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220912
PL  - United States
TA  - Nat Struct Mol Biol
JT  - Nature structural & molecular biology
JID - 101186374
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Basic Helix-Loop-Helix Transcription Factors/*metabolism
MH  - Humans
MH  - *Kidney Neoplasms/genetics
MH  - Oxygen
MH  - Protein Isoforms
MH  - RNA, Messenger/genetics/metabolism
MH  - Ribosomes/metabolism
MH  - *TOR Serine-Threonine Kinases
PMC - PMC9507966
COIS- P. J. R. is a scientific co-founder and equity holder in ReOx Ltd. He is a 
      non-executive director of Immunocore Ltd and holds a consultancy with IDP 
      Discovery Pharma SL. Y. S. declares no competing interests.
EDAT- 2022/09/14 06:00
MHDA- 2022/09/28 06:00
PMCR- 2022/09/12
CRDT- 2022/09/13 00:13
PHST- 2021/07/06 00:00 [received]
PHST- 2022/07/15 00:00 [accepted]
PHST- 2022/09/14 06:00 [pubmed]
PHST- 2022/09/28 06:00 [medline]
PHST- 2022/09/13 00:13 [entrez]
PHST- 2022/09/12 00:00 [pmc-release]
AID - 10.1038/s41594-022-00819-2 [pii]
AID - 819 [pii]
AID - 10.1038/s41594-022-00819-2 [doi]
PST - ppublish
SO  - Nat Struct Mol Biol. 2022 Sep;29(9):871-880. doi: 10.1038/s41594-022-00819-2. 
      Epub 2022 Sep 12.