Shin Sook, Rossow Kari L, Grande Joseph P, Janknecht Ralf
Department of Biochemistry, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Cancer Res. 2007 Aug 15;67(16):7572-8. doi: 10.1158/0008-5472.CAN-06-4652.
The homologous proteins p68 and p72 are members of the DEAD box family of RNA helicases. Here, we show that expression of both of these helicases strongly increases during the polyp-->adenoma-->adenocarcinoma transition in the colon. Furthermore, p68 and p72 form complexes with beta-catenin and promote the ability of beta-catenin to activate gene transcription. Conversely, simultaneous knockdown of p68 and p72 leads to reduced expression of the beta-catenin-regulated genes, c-Myc, cyclin D1, c-jun, and fra-1, all of which are proto-oncogenes. Moreover, transcription of the cell cycle inhibitor p21(WAF1/CIP1), whose expression is suppressed by c-Myc, is enhanced on p68/p72 knockdown. Thus, p68/p72 may contribute to colon cancer formation by directly up-regulating proto-oncogenes and indirectly by down-regulating the growth suppressor p21(WAF1/CIP1). Accordingly, knockdown of p68 and p72 in colon cancer cells inhibits their proliferation and diminishes their ability to form tumors in vivo. Altogether, these results suggest that p68/p72 overexpression is not only a potential marker of colon cancer but is also causally linked to this disease. Therefore, p68 and p72 may be novel targets in the combat against colon cancer.
同源蛋白p68和p72是RNA解旋酶DEAD盒家族的成员。在此，我们表明，在结肠息肉→腺瘤→腺癌的转变过程中，这两种解旋酶的表达均显著增加。此外，p68和p72与β-连环蛋白形成复合物，并增强β-连环蛋白激活基因转录的能力。相反，同时敲低p68和p72会导致β-连环蛋白调节的基因c-Myc、细胞周期蛋白D1、c-jun和fra-1的表达降低，所有这些都是原癌基因。此外，细胞周期抑制剂p21（WAF1/CIP1）的转录在敲低p68/p72后增强，其表达受c-Myc抑制。因此，p68/p72可能通过直接上调原癌基因和间接下调生长抑制因子p21（WAF1/CIP1）促进结肠癌的形成。相应地，在结肠癌细胞中敲低p68和p72可抑制其增殖，并降低其在体内形成肿瘤的能力。总之，这些结果表明，p68/p72过表达不仅是结肠癌的潜在标志物，而且与该疾病存在因果关系。因此，p68和p72可能是对抗结肠癌的新靶点。
