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Annexin A2 Mediates Up-regulation of NF-kappa B, beta-catenin, and Stem Cell in Response to Progastrin in Mice and HEK-293 Cells

  作者 Sarkar, S; Swiercz, R; Kantara, C; Hajjar, KA; Singh, P  
  选自 期刊  Gastroenterology;  卷期  2011年140-2;  页码  583-U312  
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[摘要]BACKGROUND & AIMS: Prograstrin induces proliferation in colon crypts by activating p65nuclear factor-kappa B (NF-kappa B) (p65) and beta-catenin. We investigated whether Annexin A2 (AnxA2), a progastrin receptor, activates NF-kappa B and beta-catenin in vivo. METHODS: ANXA2-null (ANXA2(-/-)) and wild-type (ANXA2(+/+)) mice were studied, along with clones of progastrin-responsive HEK-293 cells that stably expressed full-length progastrin (HEK-mGAS) or an empty vector (HEK-C). Small interfering RNA was used to down-regulate AnxA2, p65NF-kappa B, and beta-catenin in cells. RESULTS: Proliferation and activation of p65 and beta-catenin increased significantly in HEK-mGAS compared with HEK-C clones. HEK-mGAS cells had a 2- to 4-fold increase in relative levels of c-Myc, cyclooxygenase (COX)-2, CyclinD1, double cortin CAM kinase-like 1 (DCAMKL+1), and CD44, compared with HEK-C clones. Down-regulation of AnxA2 in HEK-mGAS clones reduced activation of NF-kappa B and beta-catenin, as well as levels of DCAMKL+1. Surprisingly, down-regulation of beta-catenin had no effect on activation of p65NF-kappa B, whereas down-regulation of p65 significantly reduced activation of beta-catenin in HEK-mGAS clones. Loss of either p65 or beta-catenin significantly reduced proliferation of HEK-mGAS clones, indicating that both factors are required for the proliferative effects of progastrin. Lengths of colon crypts and levels of p65, beta-catenin, DCAMKL+1, and CD44 were significantly higher in ANXA2(+/+) mice compared with either ANXA2(-/-) mice given progastrin or ANXA2(+/+) and ANXA2(-/-) mice given saline. CONCLUSIONS: AnxA2 expression is required for the biologic effects of progastrin in vivo and in vitro and mediates the stimulatory effect of progastrin on p65NF-kappa, beta-catenin, and the putative stem cell markers DCAMKL+1 and CD44. AnxA2 might therefore mediate the hyperproliferative and cocarcinogenic effects of progastrin.

 
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