Cyclin D1 activation through ATF-2 in Reg-induced pancreatic beta-cell regeneration.
Regenerating gene product (Reg) is induced in pancreatic beta-cells and acts as an autocrine/paracrine growth factor for regeneration via a cell surface Reg receptor. However, the manner by which Reg induces beta-cell regeneration was unknown. In the present study, we found that Reg increased phospho-ATF-2, which binds to -57 to -52 of the cyclin D1 gene to activate the promoter. The Reg/ATF-2-induced cyclin D1 promoter activation was attenuated by PI(3)K inhibitors such as LY294002 and wortmannin. In Reg knockout mouse islets, the levels of phospho-ATF-2, cyclin D1, and phospho-Rb were greatly decreased. These results indicate that the Reg-Reg receptor system stimulates the PI(3)K/ATF-2/cyclin D1 signaling pathway to induce beta-cell regeneration.
Takasawa
Shin
S
Department of Biochemistry, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai 980-8575, Japan.
Ikeda
Takayuki
T
Akiyama
Takako
T
Nata
Koji
K
Nakagawa
Kei
K
Shervani
Nausheen J
NJ
Noguchi
Naoya
N
Murakami-Kawaguchi
Shoko
S
Yamauchi
Akiyo
A
Takahashi
Iwao
I
Tomioka-Kumagai
Tomoko
T
Okamoto
Hiroshi
H
D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D037181:Lectins, C-Type / Q000378:metabolism; D051847:Lithostathine / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012038:Regeneration; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D051698:Activating Transcription Factor 2; C497106:Atf2 protein, mouse; D037181:Lectins, C-Type; D051847:Lithostathine; C469954:Reg receptor, human; D016160:Retinoblastoma Protein; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases