title: Bidirectional autoregulatory mechanism of metastasis-associated protein 1-alternative reading frame pathway in oncogenesis.
abstract: Although metastasis-associated protein 1 (MTA1), a component of the nucleosome remodeling and histone deacetylation complex, is widely up-regulated in human cancers and correlates with tumor metastasis, its regulatory mechanism and related signaling pathways remain unknown. Here, we report a previously unrecognized bidirectional autoregulatory loop between MTA1 and tumor suppressor alternative reading frame (ARF). MTA1 transactivates ARF transcription by recruiting the transcription factor c-Jun onto the ARF promoter in a p53-independent manner. ARF, in turn, negatively regulates MTA1 expression independently of p53 and c-Myc. In this context, ARF interacts with transcription factor specificity protein 1 (SP1) and promotes its proteasomal degradation by enhancing its interaction with proteasome subunit regulatory particle ATPase 6, thereby abrogating the ability of SP1 to stimulate MTA1 transcription. ARF also physically associates with MTA1 and affects its protein stability. Thus, MTA1-mediated activation of ARF and ARF-mediated functional inhibition of MTA1 represent a p53-independent bidirectional autoregulatory mechanism in which these two opposites act in concert to regulate cell homeostasis and oncogenesis, depending on the cellular context and the environment.
authors.affiliation: Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037, USA.
authors.forename: Da-Qiang
authors.initials: DQ
authors.lastname: Li
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Pakala
authors.forename: Sirigiri Divijendra Natha
authors.initials: SD
authors.lastname: Reddy
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Ohshiro
authors.forename: Jun-Xiang
authors.initials: JX
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Yanping
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ignacio
authors.initials: I
authors.lastname: Moreno de Alborán
authors.forename: M Radhakrishna
authors.initials: MR
authors.lastname: Pillai
authors.forename: Jeyanthy
authors.initials: J
authors.lastname: Eswaran
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
mesh_terms: D002460:Cell Line; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics*; D006801:Humans; D009369:Neoplasms / Q000209:etiology*; D016364:Reading Frames; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C089320:MTA1 protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D006655:Histone Deacetylases