PMID- 30012886
OWN - NLM
STAT- MEDLINE
DCOM- 20190409
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 293
IP  - 37
DP  - 2018 Sep 14
TI  - Functional proteasome complex is required for turnover of islet amyloid 
      polypeptide in pancreatic beta-cells.
PG  - 14210-14223
LID - 10.1074/jbc.RA118.002414 [doi]
AB  - Human islet amyloid polypeptide (hIAPP) is the principal constituent of amyloid 
      deposits and toxic oligomers in the pancreatic islets. Together with 
      hyperglycemia, hIAPP-derived oligomers and aggregates are important culprits in 
      type 2 diabetes mellitus (T2DM). Here, we explored the role of the cell's main 
      proteolytic complex, the proteasome, in hIAPP turnover in normal and stressed 
      beta-cells evoked by chronic hyperglycemia. Moderate inhibition (10-35%) of 
      proteasome activity/function in cultured human islets by the proteasome inhibitor 
      lactacystin enhanced intracellular accumulation of hIAPP. Unexpectedly, prolonged 
      (>1 h) and marked (>50%) impairment of proteasome activity/function had a strong 
      inhibitory effect on hIAPP transcription and secretion from normal and stressed 
      beta-cells. This negative compensatory feedback mechanism for controlling IAPP 
      turnover was also observed in the lactacystin-treated rat insulinoma beta-cell line 
      (INS 832/13), demonstrating the presence of an evolutionarily conserved mechanism 
      for IAPP production. In line with these in situ studies, our current ex vivo data 
      showed that proteasome activity and hIAPP expression are also down-regulated in 
      islets isolated from T2DM subjects. Gene expression and promoter activity studies 
      demonstrated that the functional proteasome complex is required for efficient 
      activation of the hIAPP promoter and for full expression of IAPP's essential 
      transcription factor, FOXA2. ChIP studies revealed that promoter occupancy of 
      FoxA2 at the rat IAPP promoter region is an important and limiting factor for 
      amylin expression in proteasome-impaired murine cells. This study suggests a 
      novel regulatory pathway in beta-cells involving proteasome, FOXA2, and IAPP, which 
      can be possibly targeted to regulate hIAPP levels and islet amyloidosis in T2DM.
CI  - (c) 2018 Chatterjee Bhowmick and Jeremic.
FAU - Chatterjee Bhowmick, Diti
AU  - Chatterjee Bhowmick D
AD  - From the Departments of Biological Sciences and Biomedical Sciences, George 
      Washington University, Washington, D. C. 20052.
FAU - Jeremic, Aleksandar
AU  - Jeremic A
AD  - From the Departments of Biological Sciences and Biomedical Sciences, George 
      Washington University, Washington, D. C. 20052 jerema@gwu.edu.
LA  - eng
GR  - R01 DK091845/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180716
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (FOXA2 protein, human)
RN  - 0 (Islet Amyloid Polypeptide)
RN  - 0 (Leupeptins)
RN  - 0 (Oligopeptides)
RN  - 0 (Proteasome Inhibitors)
RN  - 133343-34-7 (lactacystin)
RN  - 135845-92-0 (Hepatocyte Nuclear Factor 3-beta)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde)
RN  - WYQ7N0BPYC (Acetylcysteine)
RN  - Y0900I3U8U (epoxomicin)
SB  - IM
MH  - Acetylcysteine/analogs & derivatives/pharmacology
MH  - Animals
MH  - Cell Line, Tumor
MH  - Diabetes Mellitus, Type 2/*metabolism/pathology
MH  - Down-Regulation
MH  - Hepatocyte Nuclear Factor 3-beta/metabolism
MH  - Humans
MH  - Insulin-Secreting Cells/enzymology/*metabolism
MH  - Insulinoma/enzymology/metabolism
MH  - Islet Amyloid Polypeptide/genetics/*metabolism
MH  - Leupeptins/pharmacology
MH  - Mice
MH  - Oligopeptides/pharmacology
MH  - Promoter Regions, Genetic
MH  - Proteasome Endopeptidase Complex/drug effects/*metabolism
MH  - Proteasome Inhibitors/pharmacology
MH  - Rats
PMC - PMC6139561
OTO - NOTNLM
OT  - FoxA2
OT  - Islet amyloid polypeptide
OT  - amyloid
OT  - hyperglycemia
OT  - insulin
OT  - proteasome
OT  - secretion
OT  - transcription
OT  - type 2 diabetes
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2018/07/18 06:00
MHDA- 2019/04/10 06:00
PMCR- 2019/09/14
CRDT- 2018/07/18 06:00
PHST- 2018/02/12 00:00 [received]
PHST- 2018/07/02 00:00 [revised]
PHST- 2018/07/18 06:00 [pubmed]
PHST- 2019/04/10 06:00 [medline]
PHST- 2018/07/18 06:00 [entrez]
PHST- 2019/09/14 00:00 [pmc-release]
AID - S0021-9258(20)30895-4 [pii]
AID - RA118.002414 [pii]
AID - 10.1074/jbc.RA118.002414 [doi]
PST - ppublish
SO  - J Biol Chem. 2018 Sep 14;293(37):14210-14223. doi: 10.1074/jbc.RA118.002414. Epub 
      2018 Jul 16.