Modulator of apoptosis 1 (MOAP-1) is a tumor suppressor protein linked to the RASSF1A protein.
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, immunoblotting of cancer cells, proliferation, and xenograft assays as well as DNA microarray analysis to demonstrate the role of MOAP-1 as a tumor suppressor protein. Frequent loss of MOAP-1 expression, in at least some cancers, appears to be attributed to mRNA down-regulation and the rapid proteasomal degradation of MOAP-1 that could be reversed utilizing the proteasome inhibitor MG132. Overexpression of MOAP-1 in several cancer cell lines resulted in reduced tumorigenesis and up-regulation of genes involved in cancer regulatory pathways that include apoptosis (p53, Fas, and MST1), DNA damage control (poly(ADP)-ribose polymerase and ataxia telangiectasia mutated), those within the cell metabolism (IR-α, IR-β, and AMP-activated protein kinase), and a stabilizing effect on microtubules. The loss of RASSF1A (an upstream regulator of MOAP-1) is one of the earliest detectable epigenetically silenced tumor suppressor proteins in cancer, and we speculate that the additional loss of function of MOAP-1 may be a second hit to functionally compromise the RASSF1A/MOAP-1 death receptor-dependent pathway and drive tumorigenesis.
From the Departments of Biochemistry and.
Jennifer
J
Law
From the Departments of Biochemistry and.
Mohamed
M
Salla
Pediatrics.
Alaa
A
Zare
From the Departments of Biochemistry and.
Yoke
Y
Wong
From the Departments of Biochemistry and.
Le
L
Luong
From the Departments of Biochemistry and.
Natalia
N
Volodko
From the Departments of Biochemistry and.
Orysya
O
Svystun
From the Departments of Biochemistry and.
Kayla
K
Flood
From the Departments of Biochemistry and.
Jonathan
J
Lim
Pediatrics, Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
Miranda
M
Sung
Pediatrics, Cardiovascular Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
Jason R B
JR
Dyck
the Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
Chong Teik
CT
Tan
the Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
Yu-Chin
YC
Su
the Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore 117543, Singapore.
Victor C
VC
Yu
the Department of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada, and.
John
J
Mackey
From the Departments of Biochemistry and Pediatrics, the Department of Experimental Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta T6G 1Z2, Canada, and the Cancer Research Institute of Northern Alberta, Edmonton, Alberta T6G 1Z2, Canada, the Alberta IBD Consortium, Edmonton, Alberta T6G 2X8, Canada, and the Women and Children's Health Research Institute, Edmonton, Alberta T6G 1C9, Canada sbaksh@ualberta.ca.
Shairaz
S
Baksh
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004249:DNA Damage; D044127:Epigenesis, Genetic; D005260:Female; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D055106:Genome-Wide Association Study; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C428449:MOAP1 protein, human; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D051028:bcl-2-Associated X Protein
Bax; GWAS; Rassf1a; apoptosis; cancer; moap-1; tubulin; tumor suppressor gene; ubiquitylation (ubiquitination)