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.

The translationally controlled tumor protein (TCTP) is a highly conserved multifunctional protein, preferentially expressed in mitotically active tissues and is a potential biomarker and a therapeutic target for lung cancers. An understanding of the biology of this molecule and model systems for the screening of drugs is still awaited. In the absence of complete crystal structure, NMR structures as templates were used for homology modeling and MD optimization of both Dictyostelium discoideum and human TCTPs, which was followed by pocket-site prediction, ligand screening and docking. Rescoring of TCTP–ligand complexes was done using MD and MM-PBSA approaches. D. discoideum TCTP was expressed under a constitutive promoter and the endogenous RNA in multicellular structures formed was localized by in situ hybridization. Based on the interactions and binding energy scores, two novel compounds were identified as the best potential inhibitors that could be further used for the development of drug candidates. Inhibition of cell proliferation was observed in the strain overexpressing Dictyostelium TCTP and in situ hybridization results show them to be localized in the prestalk (dying cell population) cells. D. discoideum and human TCTPs share similar dynamic behaviors; overexpression of Dictyostelium TCTP inhibits cell proliferation. D. discoideum could be used as a model system for understanding the biology of this molecule and also for drug screening.