Rap2a is a novel target gene of p53 and regulates cancer cell migration and invasion.
The p53 transcription factor is a critical regulator of the cell cycle, DNA repair, and apoptosis. Recent evidences suggest that p53 may contribute to the regulation of cell invasion and migration. Rap2a, a member of the small GTPase superfamily, mediates diverse cellular events such as cell adhesion, migration and proliferation through various signaling pathways. In this study, we identify that Rap2a is a novel target of p53 and is induced upon DNA damage in a p53-dependent manner. Upon DNA damage, p53 directly binds to the promoter of Rap2a and activates its transcription. We show that Rap2a is significantly upregulated in many types of tumors. In addition, the ectopic expression of Rap2a enhances the migration and invasive ability of cancer cells and increases activities of matrix metalloproteinase MMP2 and MMP9. In contrast, the inactivation of Rap2a inhibits cell invasion and activities of MMP2 and MMP9. We also show that Rap2a regulates the phosphorylation level of Akt. Collectively, our results show that ectopic expression of Rap2a has a key role in enhancing migration, invasion and metastasis by upregulating p-Akt.
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China.
Jin-Xia
JX
Wu
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China.
Ding-Guo
DG
Zhang
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical College, Xuzhou 221002, China. Electronic address: jnzheng@xzmc.edu.cn.
Jun-Nian
JN
Zheng
Jiangsu Key Laboratory of Biological Cancer Therapy, Xuzhou Medical College, Xuzhou 221002, China. Electronic address: dspei@xzmc.edu.cn.
Dong-Sheng
DS
Pei
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D020668:rap GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C116756:RAP2A protein, human; D020668:rap GTP-Binding Proteins; D002945:Cisplatin
Invasion; Migration; Rap2a; p-Akt; p53