title: Apaf-1 is a transcriptional target for E2F and p53.
abstract: Loss of function of the retinoblastoma protein, pRB, leads to lack of differentiation, hyperproliferation and apoptosis. Inactivation of pRB results in deregulated E2F activity, which in turn induces entry to S-phase and apoptosis. Induction of apoptosis by either the loss of pRB or the deregulation of E2F activity occurs via both p53-dependent and p53-independent mechanisms. The mechanism by which E2F induces apoptosis is still unclear. Here we show that E2F1 directly regulates the expression of Apaf-1, the gene for apoptosis protease-activating factor 1. These results provide a direct link between the deregulation of the pRB pathway and apoptosis. Furthermore, because the pRB pathway is functionally inactivated in most cancers, the identification of Apaf-1 as a transcriptional target for E2F might explain the increased sensitivity of tumour cells to chemotherapy. We also show that, independently of the pRB pathway, Apaf-1 is a direct transcriptional target of p53, suggesting that p53 might sensitize cells to apoptosis by increasing Apaf-1 levels.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Moroni
authors.forename: E S
authors.initials: ES
authors.lastname: Hickman
authors.forename: E
authors.initials: E
authors.lastname: Lazzerini Denchi
authors.forename: G
authors.initials: G
authors.lastname: Caprara
authors.forename: E
authors.initials: E
authors.lastname: Colli
authors.forename: F
authors.initials: F
authors.lastname: Cecconi
authors.forename: H
authors.initials: H
authors.lastname: Müller
authors.forename: K
authors.initials: K
authors.lastname: Helin
mesh_terms: D000818:Animals; D053477:Apoptotic Protease-Activating Factor 1; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D004622:Embryo, Mammalian / Q000378:metabolism; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C506592:APAF1 protein, human; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C493754:E2f1 protein, mouse; D011506:Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53