PMID- 28410006
OWN - NLM
STAT- MEDLINE
DCOM- 20180329
LR  - 20200403
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 13
IP  - 5
DP  - 2017 May 4
TI  - Chaperone-mediated autophagy prevents cellular transformation by regulating MYC 
      proteasomal degradation.
PG  - 928-940
LID - 10.1080/15548627.2017.1293767 [doi]
AB  - Chaperone-mediated autophagy (CMA), a selective form of protein lysosomal 
      degradation, is maximally activated in stress situations to ensure maintenance of 
      cellular homeostasis. CMA activity decreases with age and in several human 
      chronic disorders, but in contrast, in most cancer cells, CMA is upregulated and 
      required for tumor growth. However, the role of CMA in malignant transformation 
      remains unknown. In this study, we demonstrate that CMA inhibition in fibroblasts 
      augments the efficiency of MYC/c-Myc-driven cellular transformation. CMA blockage 
      contributes to the increase of total and nuclear MYC, leading to enhancement of 
      cell proliferation and colony formation. Impaired CMA functionality accentuates 
      tumorigenesis-related metabolic changes observed upon MYC-transformation. 
      Although not a direct CMA substrate, we have found that CMA regulates cellular 
      MYC levels by controlling its proteasomal degradation. CMA promotes MYC 
      ubiquitination and degradation by regulating the degradation of 
      C330027C09Rik/KIAA1524/CIP2A (referred to hereafter as CIP2A), responsible for 
      MYC stabilization. Ubiquitination and proteasomal degradation of MYC requires 
      dephosphorylation at Ser62, and CIP2A inhibits the phosphatase responsible for 
      this dephosphorylation. Failure to degrade CIP2A upon CMA blockage leads to 
      increased levels of phosphorylated MYC (Ser62) and to stabilization of this 
      oncogene. We demonstrate that this phosphorylation is essential for the 
      CMA-mediated effect, since specific mutation of this site (Ser62 to Ala62) is 
      enough to normalize MYC levels in CMA-incompetent cells. Altogether these data 
      demonstrate that CMA mitigates MYC oncogenic activity by promoting its 
      proteasomal degradation and reveal a novel tumor suppressive role for CMA in 
      nontumorigenic cells.
FAU - Gomes, Luciana R
AU  - Gomes LR
AD  - a Department of Developmental and Molecular Biology and Institute for Aging 
      Studies , Albert Einstein College of Medicine , Bronx , NY , USA.
AD  - b Department of Microbiology , Institute of Biomedical Sciences, University of 
      Sao Paulo , Sao Paulo , SP , Brazil.
FAU - Menck, Carlos F M
AU  - Menck CFM
AD  - b Department of Microbiology , Institute of Biomedical Sciences, University of 
      Sao Paulo , Sao Paulo , SP , Brazil.
FAU - Cuervo, Ana Maria
AU  - Cuervo AM
AD  - a Department of Developmental and Molecular Biology and Institute for Aging 
      Studies , Albert Einstein College of Medicine , Bronx , NY , USA.
LA  - eng
GR  - P30 DK041296/DK/NIDDK NIH HHS/United States
GR  - R37 AG021904/AG/NIA NIH HHS/United States
GR  - P30 DK020541/DK/NIDDK NIH HHS/United States
GR  - P30 AG038072/AG/NIA NIH HHS/United States
GR  - R01 DK098408/DK/NIDDK NIH HHS/United States
GR  - P01 AG031782/AG/NIA NIH HHS/United States
PT  - Journal Article
DEP - 20170302
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Molecular Chaperones)
RN  - 0 (Proto-Oncogene Proteins c-myc)
SB  - IM
MH  - Animals
MH  - Autophagy/*physiology
MH  - Cell Proliferation/*physiology
MH  - Fibroblasts/metabolism
MH  - Lysosomes/*metabolism
MH  - Mice
MH  - Molecular Chaperones/*metabolism
MH  - Neoplasms/metabolism
MH  - Proto-Oncogene Proteins c-myc/metabolism
MH  - Ubiquitination/physiology
PMC - PMC5446085
OTO - NOTNLM
OT  - Autophagy
OT  - CIP2A
OT  - cancer
OT  - lysosomes
OT  - oncogene
OT  - proteolysis
EDAT- 2017/04/15 06:00
MHDA- 2018/03/30 06:00
PMCR- 2018/03/02
CRDT- 2017/04/15 06:00
PHST- 2017/04/15 06:00 [pubmed]
PHST- 2018/03/30 06:00 [medline]
PHST- 2017/04/15 06:00 [entrez]
PHST- 2018/03/02 00:00 [pmc-release]
AID - 1293767 [pii]
AID - 10.1080/15548627.2017.1293767 [doi]
PST - ppublish
SO  - Autophagy. 2017 May 4;13(5):928-940. doi: 10.1080/15548627.2017.1293767. Epub 
      2017 Mar 2.