Ubiquitously expressed hematological and neurological expressed 1 downregulates Akt-mediated GSK3ß signaling, and its knockdown results in deregulated G2/M transition in prostate cells
Küçük Resim Yok
Tarih
2011
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
As the molecular mechanism of ß-catenin deregulation is not well understood, and stabilized ß-catenin is known to translocate into the nucleus and activate genes for proliferation, a novel regulatory factor, hematological and neurological expressed 1 (HN1), for Akt-GSK3ß-ß- catenin axis is reported here. In our studies, HN1 gene structure was characterized. HN1 expression was found to be epidermal growth factor-responsive in PC-3 cells, and protein expression was also upregulated in PC-3 and LNCaP but not in DU145 cells. Additionally, HN1 was found to be downregulated by the specific AKT inhibitor wortmannin but not with PI3K or MAPK inhibitors, LY294002 and PD98059, respectively, in PC-3 and MCF-7 cells. Further, siRNA-mediated knockdown of HN1 resulted in considerable increase in Akt (S473) and GSK3ß (S9),(Y216) phosphorylations; moreover, subsequent accumulation of ß-catenin, increase in c-myc expression, and nuclear accumulation of cyclin D1 were observed in PC-3 cells. Knockdown of HN1 also resulted in prolongation of G 1 phase in cell cycle, increasing tetraploidy, presumably because of cells escaping from abnormal mitosis in PC-3 cells. Consistently, overexpression of HN1 reversed the cell-cycle-specific observations, resulted in accumulation of cells in G 2/M, and reduced the proliferation rate, which were investigated using flow cytometry and methylthiazol tetrazolium assays. As activating mutations of ß-catenin have been demonstrated in late-stage tumors, and ß-catenin stabilization was correlated with poor prognosis in previous reports, epidermal growth factor-upregulated HN1 expression might have a role in deregulating the AKT-GSK3ß (S9)-mediated signaling as a novel compensating mechanism. © 2011 Mary Ann Liebert, Inc.
Açıklama
Anahtar Kelimeler
Kaynak
DNA and Cell Biology
WoS Q Değeri
Scopus Q Değeri
Q2
Cilt
30
Sayı
6
