Abstract LB-067: Critical role of Mieap, a p53-inducible protein, in intestinal tumor suppression

Abstract

Abstract Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria via MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole), respectively (1,2). Two mitochondrial outer membrane proteins, BNIP3 and NIX are essential mediators of MALM (3). 14-3-3gamma mediates the degradation of oxidized mitochondrial proteins in the MALM function (4). The Mieap-regulated mitochondrial quality control pathway was inactivated in almost 80% of colorectal cancer patients (5). Here, we report that Mieap plays a critical role in mouse intestinal tumor suppression. To investigate a role of Mieap in intestinal tumorigenesis, we generated the Mieap-deficient ApcMIN/+ mice. The ApcMIN/+ mice with the Mieap+/− and Mieap−/− genetic background revealed the remarkable shortening of the lifetime, compared to ApcMIN/+ mice. Mieap deficiency caused the increased number and size of the intestinal tumors in ApcMIN/+ mice. In addition, the tumors in the Mieap-deficient ApcMIN/+ mice showed more advanced grade of malignancy and often became cancerous. The mitochondria in the intestine and tumor of the Mieap-deficient ApcMIN/+ mice were morphologically unhealthy and generated high level of reactive oxygen species. These results suggest that Mieap plays a critical role in intestinal tumor suppression through mitochondrial quality control and prevention of mitochondrial oxidative stress. The Mieap-regulated mitochondrial quality control is a critical function for p53 tumor suppressor. (1) 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. This paper was highly evaluated by F1000 (Must Read, Rating 8; Evaluated by Rial E: 2011. F1000.com/8253956) (2) Kitamura N, Nakamura Y, Miyamoto Y, Miyamoto T, Kabu K, Yoshida M, Futamura M, Ichinose S, Arakawa H. Mieap, a p53-indicuble protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. PLoS ONE 6: e16060, 2011. (3) 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. (4) Miyamoto T, Kitamura N, Ono M, Nakamura Y, Yoshida M, Kamino H, Murai R, Yamada T, Arakawa H. Identification of 14-3-3γ as a Mieap-interacting protein and its role in mitochondrial quality control. Scientific Reports 2: 379, 2012. (5) Kamino H, Nakamura Y, Kitamura N, Futamura M, Yoshida M, Murai R, Saito Y, Sano H, Kanai Y, Moriya Y, Arakawa H. Frequent inactivation of the Mieap-regulated mitochondrial quality control in colorectal cancer. AACR annual meeting 2013 (Washington D.C.): abstract number 1687 Citation Format: Yasuyuki Nakamura, Masayuki Tsuneki, Takashi Kinjyo, Noriaki Kitamura, Hirofumi Arakawa. Critical role of Mieap, a p53-inducible protein, in intestinal tumor suppression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-067. doi:10.1158/1538-7445.AM2015-LB-067