Di Bacco Alessandra, Gill Grace
Department of Pathology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115, USA.
Oncogene. 2003 Aug 21;22(35):5436-45. doi: 10.1038/sj.onc.1206670.
Secreted proteins and their cognate receptors are implicated in a myriad of activities that regulate cell proliferation, differentiation, and development. CREG, a cellular repressor of E1A-stimulated genes, is a secreted glycoprotein that antagonizes cellular transformation by E1A and ras. We have previously shown that CREG expression is induced very early during differentiation of pluripotent cells and, even in the absence of other inducers, CREG promotes neuronal differentiation of human teratocarcinoma NTERA-2 cells. Here we show that ectopic expression of CREG in NTERA-2 cells results in a delay of the G1/S phase transition of the cell cycle and growth inhibition. We show that CREG binds directly to the mannose-6-phosphate/insulin-like growth factor II receptor (M6P/IGF2R) dependent on CREG glycosylation. The M6P/IGF2R is a tumor suppressor that functions to control cell growth through interactions with multiple ligands. By analysing CREG activity in cells lacking M6P/IGF2R expression, we show that this receptor is required for CREG-induced growth inhibition. These studies reveal that CREG inhibits cell growth dependent on the M6P/IGF2R and suggest that interactions between CREG and a well-characterized tumor suppressor may contribute to regulation of proliferation and differentiation in multiple lineages.
分泌蛋白及其同源受体参与了众多调节细胞增殖、分化和发育的活动。CREG是E1A刺激基因的细胞抑制因子，是一种分泌型糖蛋白，可拮抗E1A和ras诱导的细胞转化。我们之前已经表明，在多能细胞分化的早期就会诱导CREG表达，并且即使在没有其他诱导剂的情况下，CREG也能促进人畸胎瘤NTERA-2细胞的神经元分化。在此我们表明，在NTERA-2细胞中异位表达CREG会导致细胞周期的G1/S期转换延迟并抑制生长。我们发现，CREG依赖其糖基化直接与甘露糖-6-磷酸/胰岛素样生长因子II受体（M6P/IGF2R）结合。M6P/IGF2R是一种肿瘤抑制因子，通过与多种配体相互作用来控制细胞生长。通过分析缺乏M6P/IGF2R表达的细胞中的CREG活性，我们发现该受体是CREG诱导生长抑制所必需的。这些研究表明，CREG依赖M6P/IGF2R抑制细胞生长，并提示CREG与一种已明确的肿瘤抑制因子之间的相互作用可能有助于调节多个谱系中的增殖和分化。
