Kolligs Frank T, Nieman Marvin T, Winer Ira, Hu Gang, Van Mater David, Feng Ying, Smith Ian M, Wu Rong, Zhai Yali, Cho Kathleen R, Fearon Eric R
Department of Internal Medicine, Division of Medical Genetics and the Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cancer Cell. 2002 Mar;1(2):145-55. doi: 10.1016/s1535-6108(02)00035-1.
In many cancers, inactivation of the adenomatous polyposis coli (APC) or Axin tumor suppressor proteins or activating mutations in beta-catenin lead to elevated beta-catenin levels, enhanced binding of beta-catenin to T cell factor (TCF) proteins, and increased expression of TCF-regulated genes. We found that the gene for the basic helix-loop-helix transcription factor ITF-2 (immunoglobulin transcription factor-2) was activated in rat E1A-immortalized RK3E cells following neoplastic transformation by beta-catenin or ligand-induced activation of a beta-catenin-estrogen receptor fusion protein. Human cancers with beta-catenin regulatory defects had elevated ITF-2 expression, and ITF-2 was repressed by restoring wild-type APC function or inhibiting TCF activity. Of note, ITF-2 promoted neoplastic transformation of RK3E cells. We propose that ITF-2 is a TCF-regulated gene, which functions in concert with other TCF target genes to promote growth and/or survival of cancer cells with defects in beta-catenin regulation.
在许多癌症中，腺瘤性息肉病 coli（APC）或 Axin 肿瘤抑制蛋白失活，或β-连环蛋白中的激活突变导致β-连环蛋白水平升高、β-连环蛋白与 T 细胞因子（TCF）蛋白的结合增强以及 TCF 调控基因的表达增加。我们发现，在β-连环蛋白进行肿瘤转化或配体诱导β-连环蛋白-雌激素受体融合蛋白激活后，大鼠 E1A 永生化 RK3E 细胞中碱性螺旋-环-螺旋转录因子 ITF-2（免疫球蛋白转录因子-2）的基因被激活。具有β-连环蛋白调控缺陷的人类癌症中 ITF-2 表达升高，并且通过恢复野生型 APC 功能或抑制 TCF 活性可抑制 ITF-2。值得注意的是，ITF-2 促进了 RK3E 细胞的肿瘤转化。我们提出 ITF-2 是一个 TCF 调控基因，它与其他 TCF 靶基因协同作用，以促进β-连环蛋白调控存在缺陷的癌细胞的生长和/或存活。
