title: JAZ mediates G1 cell cycle arrest by interacting with and inhibiting E2F1.
abstract: We discovered and reported JAZ as a unique dsRNA binding zinc finger protein that functions as a direct, positive regulator of p53 transcriptional activity to mediate G1 cell cycle arrest in a mechanism involving upregulation of the p53 target gene, p21. We now find that JAZ can also negatively regulate the cell cycle in a novel, p53-independent mechanism resulting from the direct interaction with E2F1, a key intermediate in regulating cell proliferation and tumor suppression. JAZ associates with E2F1's central DNA binding/dimerization region and its C-terminal transactivation domain. Functionally, JAZ represses E2F1 transcriptional activity in association with repression of cyclin A expression and inhibition of G1/S transition. This mechanism involves JAZ-mediated inhibition of E2F1's specific DNA binding activity. JAZ directly binds E2F1 in vitro in a dsRNA-independent manner, and JAZ's dsRNA binding ZF domains, which are necessary for localizing JAZ to the nucleus, are required for repression of transcriptional activity in vivo. Importantly for specificity, siRNA-mediated "knockdown" of endogenous JAZ increases E2F transcriptional activity and releases cells from G1 arrest, indicating a necessary role for JAZ in this transition. Although JAZ can directly inhibit E2F1 activity independently of p53, if functional p53 is expressed, JAZ may exert a more potent inhibition of cell cycle following growth factor withdrawal. Therefore, JAZ plays a dual role in cell cycle regulation by both repressing E2F1 transcriptional activity and activating p53 to facilitate efficient growth arrest in response to cellular stress, which may potentially be exploited therapeutically for tumor growth inhibition.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Shands Cancer Center, University of Florida, Gainesville, FL, USA.
authors.forename: Mingli
authors.initials: M
authors.lastname: Yang
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.forename: Jinghua
authors.initials: J
authors.lastname: Jia
authors.forename: W Stratford
authors.initials: WS
authors.lastname: May
mesh_terms: D000818:Animals; D002460:Cell Line; D019925:Cyclin A / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D016193:G1 Phase; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D016335:Zinc Fingers
chemical_list: D019925:Cyclin A; D004268:DNA-Binding Proteins; D050687:E2F1 Transcription Factor; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; C485675:Zfp346 protein, mouse; D004247:DNA