The induction of STAT1 gene by activating transcription factor 3 contributes to pancreatic beta-cell apoptosis and its dysfunction in streptozotocin-treated mice.
It is well established that the IFN-gamma/STAT1 pathway plays an important role in the pancreatic beta-cell apoptosis that is observed in STZ-induced type 1 diabetes; however, the upstream regulatory proteins involved have not been understood. Here, we investigated whether activating transcription factor 3 (ATF3) affects STAT1-mediated beta-cell dysfunction and apoptosis in streptozotocin-treated mice. To this, STZ (80 mg/kg, i.p.) was administered to wild-type and STAT1(-/-) or IFN-gamma(-/-) mice for 5 days and the mice were euthanized after 14 days. STZ-induced beta-cell dysfunction and apoptosis were associated with increased STAT1/IRF-1 and ATF3 expression and were correlated with elevated IFN-gamma levels. Genetic depletion using IFN-gamma(-/-) or STAT1(-/-) mice strongly inhibited the reduction of islet cell mass or insulin synthesis/secretion and the increase of beta-cell apoptosis observed in STZ-treated wild-type mice. ATF3 overexpression, especially the C-terminal domain, strongly enhanced beta-cell dysfunction and apoptosis by enhancing STAT1 activation and its accumulation, which were abolished with an ATF3-specific siRNA or C-terminal-deleted ATF3. The STZ induction of ATF3 was completely depleted in IFN-gamma(-/-) mice, but not in STAT1(-/-) mice. Furthermore, STAT1 did not affect ATF3 expression, but STAT1 depletion or its inactivation inhibited STZ-induced ATF3 nuclear translocation and beta-cell apoptosis. Interestingly, ATF3 also increased STAT1 transcription by directly binding to a putative binding region (-116 to -96 bp) in the STAT1 promoter. Our results suggest that ATF3 functions as a potent upstream regulator of STAT1 and ATF3 may play a role in STZ-induced beta-cell dysfunction by enhancing the steady state abundance of STAT1.
Kim
Ji Yeon
JY
Division of Metabolic Diseases, Center for Biomedical Sciences, National Institutes of Health, #194 Tongillo, Eunpyeong-gu, Seoul 122-701, Republic of Korea.
Song
Eun Hyeon
EH
Lee
Sena
S
Lim
Joo Hyun
JH
Choi
Joo Sun
JS
Koh
In-uk
IU
Song
Jihyun
J
Kim
Won-Ho
WH
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
D051700:Activating Transcription Factor 3; D007328:Insulin; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma