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. MOAP-1 is part of the Ras association domain family 1A (RASSF1A)/MOAP-1 pro-apoptotic extrinsic signaling pathway that regulates apoptosis by utilizing death receptors such as tumor necrosis factor α (TNFα) or TNF-related apoptosis-inducing ligand (TRAIL) to inhibit abnormal growth. RASSF1A is a bona fide tumor suppressor gene that is epigenetically silenced by promoter-specific methylation in numerous human cancers. MOAP-1 is a downstream effector of RASSF1A that promotes Bax activation and cell death and is highly regulated during apoptosis. We speculate that MOAP-1 and RASSF1A are important elements of an “apoptotic checkpoint” that directly influences the outcome of cell death. The failure to regulate this pro-apoptotic pathway may result in the appearance of cancer and possibly other disorders. Although loss of RASSF1A expression is frequently observed in human cancers, it is currently unknown if MOAP-1 expression may also be affected during carcinogenesis to result in uncontrolled malignant growth. In this article, we will summarize what is known about the biological role(s) of MOAP-1 and how it functions as a downstream effector to RASSF1A. 1. Introduction Cancer is a disease of uncontrolled cell proliferation and is the third leading causing of death worldwide following cardiovascular and infectious diseases [2]. The abnormal proliferation of cells during cancer development results from a multistep process involving the deregulation of genes that promote cell growth (oncogenes) and those that normally function to restrain growth (tumor suppressors). Interestingly, approximately 90% of the genes that are associated with cancer development have now been identified as being tumor suppressors [3]. Moreover, many of these growth inhibitory genes encode proteins that are involved in cell death. RASSF1A has multiple biological functions including the regulation of Bax-mediated cell death [4–6]. MOAP-1, a highly regulated pro-apoptotic protein, serves a critical role during mitochondrial-dependent apoptosis by influencing and sustaining Bax activation [7, 8]. In this review, we will discuss how MOAP-1 is regulated and how it serves as a pivotal RASSF1A effector protein to regulate cell death. 2. Apoptosis: A Regulated Biological Process to Modulate Growth A well-known mechanism of tumor suppression is the elimination of unwanted cells through a sequence of events known as apoptosis [9]. The significance of
References
[1]
M. El-Kalla, C. Onyskiw, and S. Baksh, “Functional importance of RASSF1A microtubule localization and polymorphisms,” Oncogene, vol. 29, no. 42, pp. 5729–5740, 2010.
[2]
World Health Organization, The Global Burden of Disease: 2004 Update, 2008.
[3]
B. Vogelstein, The Cancer Genome, American Association for Cancer Research, Washington, DC, USA, 2010.
[4]
H. Donninger, M. D. Vos, and G. J. Clark, “The RASSF1A tumor suppressor,” Journal of Cell Science, vol. 120, no. 18, pp. 3163–3172, 2007.
[5]
S. Baksh, S. Tommasi, S. Fenton et al., “The tumor suppressor RASSF1A and MAP-1 link death receptor signaling to bax conformational change and cell death,” Molecular Cell, vol. 18, no. 6, pp. 637–650, 2005.
[6]
C. J. Foley, H. Freedman, S. L. Choo et al., “Dynamics of RASSF1A/MOAP-1 association with death receptors,” Molecular and Cellular Biology, vol. 28, no. 14, pp. 4520–4535, 2008.
[7]
K. O. Tan, K. M. L. Tan, S. L. Chan et al., “MAP-1, a novel proapoptotic protein containing a BH3-like motif that associates with bax through Its Bcl-2 homology domains,” Journal of Biological Chemistry, vol. 276, no. 4, pp. 2802–2807, 2001.
[8]
K. O. Tan, N. Y. Fu, S. K. Sukumaran et al., “MAP-1 is a mitochondrial effector of Bax,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 41, pp. 14623–14628, 2005.
[9]
C. Mondello and A. I. Scovassi, “Apoptosis: a way to maintain healthy individuals,” Sub-cellular biochemistry, vol. 50, pp. 307–323, 2010.
[10]
D. A. Carson and J. M. Ribeiro, “Apoptosis and disease,” The Lancet, vol. 341, no. 8855, pp. 1251–1254, 1993.
[11]
A. Strasser, A. W. Harris, D. C. S. Huang, P. H. Krammer, and S. Cory, “Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis,” The EMBO Journal, vol. 14, no. 24, pp. 6136–6147, 1995.
[12]
S. Elmore, “Apoptosis: a review of programmed cell death,” Toxicologic Pathology, vol. 35, no. 4, pp. 495–516, 2007.
[13]
S. J. Baker and E. P. Reddy, “Modulation of life and death by the TNF receptor superfamily,” Oncogene, vol. 17, no. 25, pp. 3261–3270, 1998.
[14]
A. Thorburn, “Death receptor-induced cell killing,” Cellular Signalling, vol. 16, no. 2, pp. 139–144, 2004.
[15]
S. W. G. Tait and D. R. Green, “Mitochondria and cell death: outer membrane permeabilization and beyond,” Nature Reviews Molecular Cell Biology, vol. 11, no. 9, pp. 621–632, 2010.
[16]
C. Wang and R. J. Youle, “The role of mitochondria in apoptosis,” Annual Review of Genetics, vol. 43, pp. 95–118, 2009.
[17]
S. L. Chan and V. C. Yu, “Proteins of the Bcl-2 family in apoptosis signalling: from mechanistic insights to therapeutic opportunities,” Clinical and Experimental Pharmacology and Physiology, vol. 31, no. 3, pp. 119–128, 2004.
[18]
S. Cory and J. M. Adams, “The BCL2 family: regulators of the cellular life-or-death switch,” Nature Reviews Cancer, vol. 2, no. 9, pp. 647–656, 2002.
[19]
R. J. Youle and A. Strasser, “The BCL-2 protein family: opposing activities that mediate cell death,” Nature Reviews Molecular Cell Biology, vol. 9, no. 1, pp. 47–59, 2008.
[20]
T. Lindsten, A. J. Ross, A. King et al., “The combined functions of proapoptotic Bcl-2 family members Bak and Bax are essential for normal development of multiple tissues,” Molecular Cell, vol. 6, no. 6, pp. 1389–1399, 2000.
[21]
M. Giam, D. C. S. Huang, and P. Bouillet, “BH3-only proteins and their roles in programmed cell death,” Oncogene, vol. 27, no. 1, pp. S128–S136, 2008.
[22]
R. Dammann, C. Li, J. H. Yoon, P. L. Chin, S. Bates, and G. P. Pfeifer, “Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3,” Nature Genetics, vol. 25, no. 3, pp. 315–319, 2000.
[23]
A. M. Richter, G. P. Pfeifer, and R. H. Dammann, “The RASSF proteins in cancer; from epigenetic silencing to functional characterization,” Biochimica et Biophysica Acta, vol. 1796, no. 2, pp. 114–128, 2009.
[24]
V. Sherwood, A. Recino, A. Jeffries, A. Ward, and A. D. Chalmers, “The N-terminal RASSF family: a new group of Ras-association-domain-containing proteins, with emerging links to cancer formation,” Biochemical Journal, vol. 425, no. 2, pp. 303–311, 2010.
[25]
N. Underhill-Day, V. Hill, and F. Latif, “N-terminal RASSF family (RASSF7-RASSF10): a mini review,” Epigenetics, vol. 6, no. 3, pp. 284–292, 2011.
[26]
L. van der Weyden and D. J. Adams, “The Ras-association domain family (RASSF) members and their role in human tumourigenesis,” Biochimica et Biophysica Acta, vol. 1776, no. 1, pp. 58–85, 2007.
[27]
G. P. Pfeifer, J. H. Yoon, L. Liu, S. Tommasi, S. P. Wilczynski, and R. Dammann, “Methylation of the RASSF1A gene in human cancers,” Biological Chemistry, vol. 383, no. 6, pp. 907–914, 2002.
[28]
A. Agathanggelou, W. N. Cooper, and F. Latif, “Role of the Ras-association domain family 1 tumor suppressor gene in human cancers,” Cancer Research, vol. 65, no. 9, pp. 3497–3508, 2005.
[29]
L. B. Hesson, W. N. Cooper, and F. Latif, “The role of RASSF1A methylation in cancer,” Disease Markers, vol. 23, no. 1-2, pp. 73–87, 2007.
[30]
R. Dammann, U. Schagdarsurengin, C. Seidel et al., “The tumor suppressor RASSF1A in human carcinogenesis: an update,” Histology and Histopathology, vol. 20, no. 2, pp. 645–663, 2005.
[31]
A. Dallol, A. Agathanggelou, S. Tommasi, G. P. Pfeifer, E. R. Maher, and F. Latif, “Involvement of the RASSF1A tumor suppressor gene in controlling cell migration,” Cancer Research, vol. 65, no. 17, pp. 7653–7659, 2005.
[32]
M. D. Vos, A. Martinez, C. Elam et al., “A role for the RASSF1A tumor suppressor in the regulation of tubulin polymerization and genomic stability,” Cancer Research, vol. 64, no. 12, pp. 4244–4250, 2004.
[33]
L. Liu, A. Vo, and W. L. McKeehan, “Specificity of the methylation-suppressed A isoform of candidate tumor suppressor RASSF1 for microtubule hyperstabilization is determined by cell death inducer C19ORF5,” Cancer Research, vol. 65, no. 5, pp. 1830–1838, 2005.
[34]
M. S. Song, J. S. Chang, S. J. Song, T. H. Yang, H. Lee, and D. S. Lim, “The centrosomal protein RAS association domain family protein 1A (RASSF1A)-binding protein 1 regulates mitotic progression by recruiting RASSF1A to spindle poles,” Journal of Biological Chemistry, vol. 280, no. 5, pp. 3920–3927, 2005.
[35]
S. L. Fenton, A. Dallol, A. Agathanggelou et al., “Identification of the E1A-regulated transcription factor p120 E4F as an interacting partner of the RASSF1A candidate tumor suppressor gene,” Cancer Research, vol. 64, no. 1, pp. 102–107, 2004.
[36]
J. Ahmed-Choudhury, A. Agathanggelou, S. L. Fenton et al., “Transcriptional regulation of cyclin A2 by RASSF1A through the enhanced binding of p120E4F to the cyclin A2 promoter,” Cancer Research, vol. 65, no. 7, pp. 2690–2697, 2005.
[37]
L. Shivakumar, J. Minna, T. Sakamaki, R. Pestell, and M. A. White, “The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation,” Molecular and Cellular Biology, vol. 22, no. 12, pp. 4309–4318, 2002.
[38]
H. J. Oh, K. K. Lee, S. J. Song et al., “Role of the tumor suppressor RASSF1A in Mst1-mediated apoptosis,” Cancer Research, vol. 66, no. 5, pp. 2562–2569, 2006.
[39]
M. Praskova, A. Khoklatchev, S. Ortiz-Vega, and J. Avruch, “Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras,” Biochemical Journal, vol. 381, no. 2, pp. 453–462, 2004.
[40]
A. Khokhlatchev, S. Rabizadeh, R. Xavier et al., “Identification of a novel Ras-regulated proapoptotic pathway,” Current Biology, vol. 12, no. 4, pp. 253–265, 2002.
[41]
D. Matallanas, D. Romano, K. Yee et al., “RASSF1A elicits apoptosis through an MST2 pathway directing proapoptotic transcription by the p73 tumor suppressor protein,” Molecular Cell, vol. 27, no. 6, pp. 962–975, 2007.
[42]
G. Halder and R. L. Johnson, “Hippo signaling: growth control and beyond,” Development, vol. 138, no. 1, pp. 9–22, 2011.
[43]
N. Y. Fu, S. K. Sukumaran, and V. C. Yu, “Inhibition of ubiquitin-mediated degradation of MOAP-1 by apoptotic stimuli promotes Bax function in mitochondria,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 24, pp. 10051–10056, 2007.
[44]
N. Rampino, H. Yamamoto, Y. Ionov et al., “Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype,” Science, vol. 275, no. 5302, pp. 967–969, 1997.
[45]
H. Yamamoto, F. Itoh, H. Fukushima et al., “Frequent bax frameshift mutations in gastric cancer with high but not low microsatellite instability,” Journal of Experimental and Clinical Cancer Research, vol. 18, no. 1, pp. 103–106, 1999.
[46]
L. C. Li and R. Dahiya, “MethPrimer: designing primers for methylation PCRs,” Bioinformatics, vol. 18, no. 11, pp. 1427–1431, 2002.
[47]
“dbSNP Short genetic variations,” NCBI, 2012, http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?showRare=on&chooseRs=coding&go=Go&locusId=64112.
X. Wei, V. Walia, J. C. Lin et al., “Exome sequencing identifies GRIN2A as frequently mutated in melanoma,” Nature Genetics, vol. 43, no. 5, pp. 442–448, 2011.
[50]
J. I. Machiya, Y. Shibata, K. Yamauchi et al., “Enhanced expression of MafB inhibits macrophage apoptosis induced by cigarette smoke exposure,” American Journal of Respiratory Cell and Molecular Biology, vol. 36, no. 4, pp. 418–426, 2007.
[51]
K. Tomita, G. Caramori, S. Lim et al., “Increased p21CIP1/WAF1 and B cell lymphoma leukemia-xL expression and reduced apoptosis in alveolar macrophages from smokers,” American Journal of Respiratory and Critical Care Medicine, vol. 166, no. 5, pp. 724–731, 2002.
[52]
H. A. Ghazaleh, R. S. Chow, S. L. Choo et al., “14-3-3 Mediated regulation of the tumor suppressor protein, RASSF1A,” Apoptosis, vol. 15, no. 2, pp. 117–127, 2010.
[53]
M. D. Vos, A. Dallol, K. Eckfeld et al., “The RASSF1A tumor suppressor activates bax via MOAP-1,” Journal of Biological Chemistry, vol. 281, no. 8, pp. 4557–4563, 2006.
[54]
N. P. C. Allen, H. Donninger, M. D. Vos et al., “RASSF6 is a novel member of the RASSF family of tumor suppressors,” Oncogene, vol. 26, no. 42, pp. 6203–6211, 2007.
[55]
S. S. Lee, N. Y. Fu, S. K. Sukumaran, K. F. Wan, Q. Wan, and V. C. Yu, “TRIM39 is a MOAP-1-binding protein that stabilizes MOAP-1 through inhibition of its poly-ubiquitination process,” Experimental Cell Research, vol. 315, no. 7, pp. 1313–1325, 2009.
[56]
K. Ozato, D. M. Shin, T. H. Chang, and H. C. Morse, “TRIM family proteins and their emerging roles in innate immunity,” Nature Reviews Immunology, vol. 8, no. 11, pp. 849–860, 2008.
[57]
R. J. Deshaies and C. A. P. Joazeiro, “RING domain E3 ubiquitin ligases,” Annual Review of Biochemistry, vol. 78, pp. 399–434, 2009.
[58]
A. F. Santidrián, D. M. González-Gironès, D. Iglesias-Serret et al., “AICAR induces apoptosis independently of AMPK and p53 through up-regulation of the BH3-only proteins BIM and NOXAin chronic lymphocytic leukemia cells,” Blood, vol. 116, no. 16, pp. 3023–3032, 2010.
[59]
F. Wang, W. Tan, D. Guo, X. Zhu, K. Qian, and S. He, “Altered expression of signaling genes in jurkat cells upon FTY720 induced apoptosis,” International Journal of Molecular Sciences, vol. 11, no. 9, pp. 3087–3105, 2010.
[60]
S. Suzuki, X. K. Li, S. Enosawa, and T. Shinomiya, “A new immunosuppressant, FTY720, induces bcl-2-associated apoptotic cell death in human lymphocytes,” Immunology, vol. 89, no. 4, pp. 518–523, 1996.
[61]
H. Azuma, S. Takahara, N. Ichimaru et al., “Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models,” Cancer Research, vol. 62, no. 5, pp. 1410–1419, 2002.
[62]
J. D. Wang, S. Takahara, N. Nonomura et al., “Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation,” Prostate, vol. 1, pp. 50–55, 1999.
[63]
T. Shinomiya, X. K. Li, H. Amemiya, and S. Suzuki, “An immunosuppressive agent, FTY720, increases intracellular concentration of calcium ion and induces apoptosis in HL-60,” Immunology, vol. 91, no. 4, pp. 594–600, 1997.
[64]
T. Matsuda, H. Nakajima, I. Fujiwara, N. Mizuta, and T. Oka, “Caspase requirement for the apoptotic death of WR19L-induced by FTY720,” Transplantation Proceedings, vol. 30, no. 5, pp. 2355–2357, 1998.
[65]
K. Musunuru and R. B. Darnell, “Paraneoplastic neurologic disease antigens: RNA-binding proteins and signaling proteins in neuronal degeneration,” Annual Review of Neuroscience, vol. 24, pp. 239–262, 2001.
[66]
W. K. Roberts and R. B. Darnell, “Neuroimmunology of the paraneoplastic neurological degenerations,” Current Opinion in Immunology, vol. 16, no. 5, pp. 616–622, 2004.
[67]
M. Schüller, D. Jenne, and R. Voltz, “The human PNMA family: novel neuronal proteins implicated in paraneoplastic neurological disease,” Journal of Neuroimmunology, vol. 169, no. 1-2, pp. 172–176, 2005.
[68]
J. Dalmau, S. H. Gultekin, R. Voltz et al., “Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders,” Brain, vol. 122, no. 1, pp. 27–39, 1999.
[69]
R. Voltz, S. H. Gultekin, M. R. Rosenfeld et al., “A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer,” The New England Journal of Medicine, vol. 340, no. 23, pp. 1788–1795, 1999.
[70]
M. R. Rosenfeld, J. G. Eichen, D. F. Wade, J. B. Posner, and J. Dalmau, “Molecular and clinical diversity in paraneoplastic immunity to Ma proteins,” Annals of Neurology, vol. 50, no. 3, pp. 339–348, 2001.
[71]
M. Takaji, Y. Komatsu, A. Watakabe, T. Hashikawa, and T. Yamamori, “Paraneoplastic antigen-like 5 gene (PNMA5) is preferentially expressed in the association areas in a primate specific manner,” Cerebral Cortex, vol. 19, no. 12, pp. 2865–2879, 2009.
[72]
L. A. Hoffmann, S. Jarius, H. L. Pellkofer et al., “Anti-Ma and anti-Ta associated paraneoplastic neurological syndromes: 22 newly diagnosed patients and review of previous cases,” Journal of Neurology, Neurosurgery and Psychiatry, vol. 79, no. 7, pp. 767–773, 2008.
[73]
H. L. Chen and S. R. D'Mello, “Induction of neuronal cell death by paraneoplastic Ma1 antigen,” Journal of Neuroscience Research, vol. 88, no. 16, pp. 3508–3519, 2010.
