PMID- 34605609
OWN - NLM
STAT- MEDLINE
DCOM- 20220314
LR  - 20220531
IS  - 1469-3178 (Electronic)
IS  - 1469-221X (Print)
IS  - 1469-221X (Linking)
VI  - 22
IP  - 12
DP  - 2021 Dec 6
TI  - Muscle-specific Cand2 is translationally upregulated by mTORC1 and promotes 
      adverse cardiac remodeling.
PG  - e52170
LID - 10.15252/embr.202052170 [doi]
LID - e52170
AB  - The mechanistic target of rapamycin (mTOR) promotes pathological remodeling in 
      the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of 
      mTOR in cardiomyocytes is protective; however, a detailed role of mTOR in 
      translational regulation of specific mRNA networks in the diseased heart is 
      unknown. We performed cardiomyocyte genome-wide sequencing to define 
      mTOR-dependent gene expression control at the level of mRNA translation. We 
      identify the muscle-specific protein Cullin-associated NEDD8-dissociated protein 
      2 (Cand2) as a translationally upregulated gene, dependent on the activity of 
      mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. 
      Mechanistically, we show that Cand2 links mTOR signaling to pathological cell 
      growth by increasing Grk5 protein expression. Our data suggest that 
      cell-type-specific targeting of mTOR might have therapeutic value against 
      pathological cardiac remodeling.
CI  - (c) 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
FAU - Gorska, Agnieszka A
AU  - Gorska AA
AUID- ORCID: 0000-0003-4667-6690
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Sandmann, Clara
AU  - Sandmann C
AUID- ORCID: 0000-0001-9115-8628
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Riechert, Eva
AU  - Riechert E
AUID- ORCID: 0000-0003-4876-7860
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Hofmann, Christoph
AU  - Hofmann C
AUID- ORCID: 0000-0002-3389-6582
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Malovrh, Ellen
AU  - Malovrh E
AUID- ORCID: 0000-0003-0911-6125
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Varma, Eshita
AU  - Varma E
AUID- ORCID: 0000-0002-9737-3406
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Kmietczyk, Vivien
AU  - Kmietczyk V
AUID- ORCID: 0000-0002-4728-4077
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Olschlager, Julie
AU  - Olschlager J
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Jurgensen, Lonny
AU  - Jurgensen L
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Kamuf-Schenk, Verena
AU  - Kamuf-Schenk V
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Stroh, Claudia
AU  - Stroh C
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Furkel, Jennifer
AU  - Furkel J
AUID- ORCID: 0000-0002-1964-4098
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Konstandin, Mathias H
AU  - Konstandin MH
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Sticht, Carsten
AU  - Sticht C
AD  - Medical Research Center, Medical Faculty Mannheim, Heidelberg University, 
      Mannheim, Germany.
FAU - Boileau, Etienne
AU  - Boileau E
AUID- ORCID: 0000-0001-9355-0973
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
AD  - Section of Bioinformatics and Systems Cardiology, Department of Cardiology, 
      Angiology, and Pneumology and Klaus Tschira Institute for Integrative 
      Computational Cardiology, University of Heidelberg, Heidelberg, Germany.
FAU - Dieterich, Christoph
AU  - Dieterich C
AUID- ORCID: 0000-0001-9468-6311
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
AD  - Section of Bioinformatics and Systems Cardiology, Department of Cardiology, 
      Angiology, and Pneumology and Klaus Tschira Institute for Integrative 
      Computational Cardiology, University of Heidelberg, Heidelberg, Germany.
FAU - Frey, Norbert
AU  - Frey N
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Katus, Hugo A
AU  - Katus HA
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Doroudgar, Shirin
AU  - Doroudgar S
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
FAU - Volkers, Mirko
AU  - Volkers M
AUID- ORCID: 0000-0003-2344-1856
AD  - Department of Cardiology, Angiology and Pneumology, University Hospital 
      Heidelberg, Heidelberg, Germany.
AD  - DZHK (German Centre for Cardiovascular Research), partner site, 
      Heidelberg/Mannheim, Germany.
LA  - eng
SI  - GEO/GSE153364
SI  - SRA/SRP156230
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211004
PL  - England
TA  - EMBO Rep
JT  - EMBO reports
JID - 100963049
RN  - 0 (CAND2 protein, human)
RN  - 0 (Muscle Proteins)
RN  - 0 (Transcription Factors)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
SB  - IM
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1/genetics/metabolism
MH  - Muscle Proteins
MH  - Myocardium/metabolism
MH  - *Myocytes, Cardiac/metabolism
MH  - Signal Transduction
MH  - Transcription Factors
MH  - Up-Regulation
MH  - *Ventricular Remodeling/genetics
PMC - PMC8647021
OTO - NOTNLM
OT  - Cand2
OT  - cardiac
OT  - hypertrophy
OT  - mTOR
COIS- All authors declare that they have no conflict of interest.
EDAT- 2021/10/05 06:00
MHDA- 2022/03/15 06:00
PMCR- 2021/10/04
CRDT- 2021/10/04 08:56
PHST- 2021/08/26 00:00 [revised]
PHST- 2020/11/29 00:00 [received]
PHST- 2021/09/10 00:00 [accepted]
PHST- 2021/10/05 06:00 [pubmed]
PHST- 2022/03/15 06:00 [medline]
PHST- 2021/10/04 08:56 [entrez]
PHST- 2021/10/04 00:00 [pmc-release]
AID - EMBR202052170 [pii]
AID - 10.15252/embr.202052170 [doi]
PST - ppublish
SO  - EMBO Rep. 2021 Dec 6;22(12):e52170. doi: 10.15252/embr.202052170. Epub 2021 Oct 
      4.