Division of Cancer Biology
The scope of our research is broad, covering numerous areas including the cloning of genes involved in carcinogenesis, biological and structural analyses of proteins, analyses of animal models and clinical samples, and the development of new strategies for cancer prevention/diagnosis/therapy.
Hirofumi Arakawa (Chief, Division of Cancer Biology) has been devoted himself to the project of “Identification and characterization of p53 target genes”, and published a number of p53 target genes involved in apoptosis, cell cycle arrest, DNA repair, anti-angiogenesis, and others（Cell 2000, Nature 2000, Molecular Cell 2001, Nature Cell Biology 2003, Nature Genetics 2003, Nature Reviews Cancer 2004, Nature Genetics 2007, Cancer Research 2007）（Figure1）.
In the process of this project, we have succeeded to discover the most important p53 target gene, designated Mieap (mitochondria-eating protein) (PLoS ONE 6: e16054, 2011). Mieap induces the accumulation of lysosomal proteins within mitochondria (MALM: Mieap-induced accumulation of lysosomal proteins within mitochondria) in response to hypoxia, and eliminates the oxidized mitochondrial proteins to repair unhealthy mitochondria. Furthermore, Mieap also induces vacuole-like structures (MIV: Mieap-induced vacuole) to eat and degrade unhealthy mitochondria. Therefore, Mieap controls mitochondrial quality by repairing or eliminating unhealthy mitochondria via MALM or MIV, respectively (PLoS ONE 6: e16060, 2011) (Figure 2). This mechanism is not mediated by canonical autophagy. Mieap-deficient ApcMin/+ mice show strikingly high rates of intestinal tumor development, and advanced graded adenomas and adenocarcinomas (Scientific Reports. 5: 12472, 2015). The p53/Mieap/BNIP3 mitochondrial quality control pathway is frequently inactivated in human clinical colorectal cancers (Oncogenesis. 5: e181, 2016). Defects in Mieap-regulated mitochondrial quality control lead to accumulation of unhealthy mitochondria in cancer cells (Figure 3). Cancer-specific unhealthy mitochondria could contribute to cancer development and aggressiveness through mitochondrial reactive oxygen species and altered metabolism (Figure 3). Therefore, Mieap-regulated mitochondrial quality control is a newly discovered function of p53 that plays a critical role in tumor suppression.
Genetic, epigenetic, molecular, cellular, animal model, and clinical analyses on the Mieap-regulated mitochondrial quality control are being performed in the Division. Our efforts could develop novel therapeutic strategies and/or biomarkers to conquer human cancer.
Figure 1. Tumor suppressor p53 regulates a large number of functions via transcriptional activation of its target genes as a transcription factor.
Figure 2. Mieap-regulated mitochondrial quality control.
Figure 3. Cancer specific unhealthy mitochondria in the hypoxic tumor microenvironment.
- Nakamura Y and Arakawa H. Discovery of Mieap-regulated mitochondrial quality control as a new function of tumor suppressor p53. Cancer Science. 108: 809-817 (2017).[PubMed]
- Kamino H, Nakamura Y, Tsuneki M, Sano H, Miyamoto Y, Kitamura N, Futamura M, Taniguchi H, Kanai Y, Shida D, Kanemitsu Y, Moriya Y, Yoshida K, Arakawa H. Mieap-regulated mitochondrial quality control is frequently inactivated in human colorectal cancer. Oncogenesis. 5: e181 (2016).[PubMed]
- Tsuneki M, Nakamura Y, Kinjo T, Nakanishi R, Arakawa H. Mieap suppresses murine intestinal tumor via its mitochondrial quality control. Scientific Reports. 5: 12472 (2015). [Times Cited: 3][PubMed]
- Miyamoto T, Kitamura N, Ono M, Nakamura Y, Yoshida M, Kamino H, Murai R, Yamada T, Arakawa H. Identification of 14-3-3gamma as a Mieap-interacting protein and its role in mitochondrial quality control. Scientific Reports. 2: 379 (2012). [Times Cited: 8][PubMed]
- Nakamura Y, Kitamura N, Shinogi D, Yoshida M, Goda O, Murai R, Kamino H, Arakawa H. BNIP3 and NIX mediate Mieap-induced accumulation of lysosomal proteins within mitochondria. PLoS ONE. 7: e30767 (2012). [Times Cited: 17][PubMed]
- Kitamura N, Nakamura Y, Miyamoto Y, Miyamoto T, Kabu K, Yoshida M, Futamura M, Ichinose S, Arakawa H. Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. PLoS ONE. 6: e16060 (2011). [Times Cited: 27][PubMed]
- Miyamoto Y, Kitamura N, Nakamura Y, Futamura M, Miyamoto T, Yoshida M, Ono M, Ichinose S, Arakawa H. Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control. PLoS ONE. 6: e16054 (2011). [Times Cited: 21][PubMed]
- Futamura M, Kamino H, Miyamoto Y, Kitamura N, Nakamura Y, Ohnishi S, Masuda Y, Arakawa H. Possible role of semaphorin 3F, a candidate tumor suppressor gene at 3p21.3, in p53-regulated tumor angiogenesis suppression. Cancer Research 67: 1451-1460 (2007). [Times Cited: 57][PubMed]
- Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chretien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, Nakamura Y, Munnich A, Rotig A. Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nature Genetics. 39: 776-780 (2007). [Times Cited: 305][PubMed]
- Arakawa H. p53, apoptosis and axon-guidance molecules. Cell Death and Differentiation. 12: 1057-1065 (2005). [Times Cited: 34][PubMed]
- Arakawa H. Netrin-1 and its receptors in tumorigenesis. Nature Reviews Cancer. 4: 978-987 (2004). [Times Cited: 128][PubMed]
- Yoon KA, Nakamura Y, Arakawa H. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. Journal of Human Genetics. 49: 134-140 (2004). [Times Cited: 130][PubMed]
- Kimura T, Takeda S, Sagiya Y, Gotoh M, Nakamura Y, Arakawa H. Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools. Nature Genetics. 34: 440-445 (2003). [Times Cited: 95][PubMed]
- Tanikawa C, Matsuda K, Fukuda S, Nakamura Y, Arakawa H. p53RDL1 regualtes p53-dependent apoptosis. Nature Cell Biology. 5: 216-223 (2003). [Times Cited: 117][PubMed]
- Ueda K, Arakawa H, Nakamura Y. Dual-specificity phosphatase 5 (DUSP5) as a direct transcriptional target for tumor suppressor p53. Oncogene 22: 5586-5591 (2003). [Times Cited: 69][PubMed]
- Ng CC, Arakawa H, Fukuda S, Kondoh H, Nakamura Y. p53RFP, a p53-inducible RING-finger protein, regulates the stability of p21WAF1. Oncogene 22: 4449-4458 (2003). [Times Cited: 33][PubMed]
- Iiizumi M, Arakawa H, Mori T, Ando A, Nakamura Y. Isolation of a novel gene, CABC1, encoding a mitochondrial protein that is highly homologous to yeast activity of bc1 complex. Cancer Research. 62: 1246-1250 (2002). [Times Cited: 36][PubMed]
- Mori T, Anazawa Y, Iiizumi M, Fukuda S, Nakamura Y, Arakawa H. Identification of the interferon regulatory factor 5 gene (IRF-5) as a direct target for p53. Oncogene. 21: 2914-2918 (2002). [Times Cited: 91][PubMed]
- Matsuda K, Yoshida K, Nakamura K, Nakamura Y, Arakawa H. p53AIP1 regulates the mitochondrial apoptotic pathway. Cancer Research. 62: 2883-2889 (2002). [Times Cited: 96][PubMed]
- Yamaguchi T, Matsuda K, Sagiya Y, Iwadate M, Fujino AJ, Nakamura Y, Arakawa H. p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint. Cancer Research. 61: 8256-8262 (2001). [Times Cited: 96][PubMed]
- Okamura S, Arakawa H, Tanaka T, Nakanishi H, Ng CC, Taya Y, Monden M, Nakamura Y. p53DINP1, a p53-Inducible Gene, Regulates p53-Dependent Apoptosis. Molecular Cell. 8: 85-94 (2001). [Times Cited: 200][PubMed]
- Shiraishi K, Fukuda S, Mori T, Matsuda K, Yamaguchi T, Tanikawa C, Ogawa M, Nakamura Y, Arakawa H. Identification of fractalkine, a CXC3-type chemokine, as a direct target of p53. Cancer Research. 60: 3722-3726 (2000). [Times Cited: 40][PubMed]
- Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser46-phosphorylated p53. Cell. 102: 849-862 (2000). [Times Cited: 882][PubMed]
- Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, Takei Y, Nakamura Y. A ribonucleotide reductase gene involved in a p53-dependent cell cycle checkpoint for DNA damage. Nature. 404: 42-49 (2000). [Times Cited: 614][PubMed]