Open AccessThe TGF ‐β‐induced up‐regulation of NKG 2 DL s requires AKT / GSK ‐3β‐mediated stabilization of SP 1
Author(s) -
Chen XiaoHui,
Lu Linlin,
Ke HongPeng,
Liu ZongCai,
Wang HaiFang,
Wei Wei,
Qi YiFei,
Wang HongSheng,
Cai ShaoHui,
Du Jun
Publication year - 2017
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13025
Subject(s) - gene knockdown , transforming growth factor , chemistry , protein kinase b , microbiology and biotechnology , receptor , pi3k/akt/mtor pathway , phosphorylation , signal transduction , biology , gene , biochemistry
Natural killer ( NK ) cells play an important role in preventing cancer development. NK group 2 member D ( NKG 2D) is an activating receptor expressed in the membrane of NK cells. Tumour cells expressing NKG 2 DL become susceptible to an immune‐dependent rejection mainly mediated by NK cells. The paradoxical roles of transforming growth factor beta ( TGF ‐β) in regulation of NKG 2 DL are presented in many studies, but the mechanism is unclear. In this study, we showed that TGF ‐β up‐regulated the expression of NKG 2 DL s in both PC 3 and HepG2 cells. The up‐regulation of NKG 2 DL s was characterized by increasing the expression of UL 16‐binding proteins ( ULBP s) 1 and 2. TGF ‐β treatment also increased the expression of transcription factor SP 1. Knockdown of SP 1 significantly attenuated TGF ‐β‐induced up‐regulation of NKG 2 DL s in PC 3 and HepG2 cells, suggesting that SP 1 plays a key role in TGF ‐β‐induced up‐regulation of NKG 2 DL s. TGF ‐β treatment rapidly increased SP 1 protein expression while not mRNA level. It might be due to that TGF ‐β can elevate SP 1 stability by activating PI 3K/ AKT signalling pathway, subsequently inhibiting GSK ‐3β activity and decreasing the association between SP 1 and GSK ‐3β. Knockdown of GSK ‐3β further verified our findings. Taken together, these results revealed that AKT / GSK ‐3β‐mediated stabilization of SP 1 is required for TGF ‐β induced up‐regulation of NKG 2 DL s. Our study provided valuable evidence for exploring the tumour immune modulation function of TGF ‐β.