The tumor suppressor maspin mediates E2F1-induced sensitivity of cancer cells to chemotherapy.
The E2F1 transcription factor is a critical downstream target of the tumor suppressor RB. When activated, E2F1 can induce cell proliferation and/or apoptosis. In addition, E2F1 overexpression sensitizes cancer cells to chemotherapeutic drugs. In a screen for genes that are regulated synergistically by E2F1 and chemotherapy in cancer cells, we identified the proapoptotic tumor suppressor gene maspin (mammary serine protease inhibitor) as a novel E2F1-regulated gene. In line with being an E2F-regulated gene, maspin expression is inhibited by short hairpin RNA directed against E2F1 and increases upon activation of endogenous E2F. Furthermore, maspin mRNA and protein levels are elevated upon activation of exogenous E2F1. Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization.
Ben Shachar
Berta
B
The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, Israel.
Feldstein
Orit
O
Hacohen
Dalia
D
Ginsberg
Doron
D
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012333:RNA, Messenger; C085344:SERPIN-B5; D015843:Serpins; D025521:Tumor Suppressor Proteins