Unknown,Transcriptomics,Genomics,Proteomics

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Modulator of Apoptosis 1 (MOAP-1) is a highly regulated tumor suppressor protein

ABSTRACT: Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in both the intrinsic and extrinsic modes of cell death or apoptosis. It is an integral partner to the tumor suppressor Ras association domain family 1A (RASSF1A) and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor is yet to be determined. In this study, we present several lines of evidence from cancer databases, immnoblotting of cancer cells, proliferation and xenograft assays to demonstrate the role of MOAP-1 as a tumor suppressor. MOAP-1 overexpressed tumors display upregulation of multiple genes including several pro-apoptotic members that may influence the role of MOAP-1 in cell death. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to enhanced proteasomal degradation. The loss of RASSF1A is an early marker of tumorigenesis and we speculate that the additional loss of function of MOAP-1 may be a second âhitâ to functionally compromise the RASSF1A/MOAP-1 death receptor dependent pathway and drive tumorigensis. RNA was isolated mouse xenographs generated with the HCT116 cell line transfected with wild type Myc-tagged MOAP-1, empty Vector or the Myc-tagged MOAP-1 mutants K278R or K264R in triplicate. Pairwise gene expression differences were compared the two samples. Features selected had more than 1.5-fold up-or down-regulated (P values of >05, unpaired Studentâs t-test).

ORGANISM(S): Homo sapiens

SUBMITTER: Kathryn Graham

PROVIDER: E-GEOD-43990 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein.

Law Jennifer J Salla Mohamed M Zare Alaa A Wong Yoke Y Luong Le L Volodko Natalia N Svystun Orysya O Flood Kayla K Lim Jonathan J Sung Miranda M Dyck Jason R B JR Tan Chong Teik CT Su Yu-Chin YC Yu Victor C VC Mackey John J Baksh Shairaz S

The Journal of biological chemistry 20150812 40

Modulator of apoptosis 1 (MOAP-1) is a BH3-like protein that plays key roles in cell death or apoptosis. It is an integral partner to the tumor suppressor protein, Ras association domain family 1A (RASSF1A), and functions to activate the Bcl-2 family pro-apoptotic protein Bax. Although RASSF1A is now considered a bona fide tumor suppressor protein, the role of MOAP-1 as a tumor suppressor protein has yet to be determined. In this study, we present several lines of evidence from cancer databases, ...[more]

PMID: 26269600

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Project description:Metastatic malignant melanoma is the deadliest skin cancer type, and it is characterized by its high resistance to apoptosis. The main driving mutations in melanoma cause hyperactivation of genes within the ERK pathway, with BRAF mutations being the most frequent ones, followed by NRAS, NF1 and MEK mutations. Increasing evidence shows that the MST2/Hippo pathway is also deregulated in this cancer type. While mutations are rare, MST2/Hippo pathway core proteins expression levels are often dysregulated in melanoma. The expression of the tumour suppressor RASSF1A, a bona fide activator of the pro-apoptotic MST2 pathway, is silenced by promoter methylation in over half of melanomas and correlates with poor prognosis. Here, using mass spectrometry-based interaction proteomics we identified Second Mitochondria-derived Activator of Caspases (SMAC) as a novel LATS1 interactor. We show that RASSF1A-dependent activation of the pro-apoptotic MST2 pathway promotes LATS1-SMAC interaction and negatively regulates the anti-apoptotic signal mediated by the members of the IAP family. Moreover, proteomic experiments identified a common cluster of the apoptotic regulator that bind to SMAC and LATS1. Mechanistic analysis show that the LATS1-SMAC complex promotes XIAP ubiquitination and its subsequent degradation which ultimately results apoptosis. Importantly, we show that the oncogenic BRAFV600E mutant prevents the pro-apoptotic signal mediated by the LAST1-SMAC complex while treatment of melanoma cell lines with BRAF inhibitors promotes this complex, indicating that inhibition of the LATS1-SMAC might be necessary for BRAFV600E-driven melanoma. Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant which requires the inhibition of C-IAP1 and the degradation of XIAP, indicating that the MST2/Hippo pathway is part of the mechanism of action of Birinapant. Overall, the current work shows SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the RAF/ERK pathway.

Dataset Information

Modulator of Apoptosis 1 (MOAP-1) is a highly regulated tumor suppressor protein

Publications

Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein.

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