Bidirectional autoregulatory mechanism of metastasis-associated protein 1-alternative reading frame pathway in oncogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 21; pp. 8791 - 8796
• Main Authors: Li, Da-Qiang, Pakala, Suresh B., Reddy, Sirigiri Divijendra Natha, Ohshiro, Kazufumi, Zhang, Jun-Xiang, Wang, Lei, Zhang, Yanping, de Alborán, Ignacio Moreno, Pillai, M. Radhakrishna, Eswaran, Jeyanthy, Kumar, Rakesh
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.05.2011; National Acad Sciences
• Subjects: adenosinetriphosphatase; Antibodies; Biological Sciences; Cancer; carcinogenesis; Cell Line; Cells; Cyclin-Dependent Kinase Inhibitor p16 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; DNA; Down regulation; Epithelial cells; Gene Expression Regulation; Genes; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; histones; Homeostasis; Homeostasis - genetics; Humans; Metastasis; neoplasms; Neoplasms - etiology; nucleosomes; nucleotide sequences; Promoter regions; proteasome endopeptidase complex; Proteins; Reading Frames; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - genetics; Repressor Proteins - metabolism; signal transduction; Trans-Activators; Transcription factors; Transcriptional Activation; Tumor Suppressor Protein p53; Tumors
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1018389108

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.