AIF Downregulation and Its Interaction with STK3 in Renal Cell Carcinoma

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 Jul 4

PMID 24992339

Citations 7

Authors

Shengqiang Xu

Hongjin Wu

Huan Nie

Lei Yue

Huadong Jiang

Sheng Xiao

Yu Li

Affiliations

Soon will be listed here.

Abstract

Apoptosis-inducing factor (AIF) plays a crucial role in caspase-independent programmed cell death by triggering chromatin condensation and DNA fragmentation. Therefore, it might be involved in cell homeostasis and tumor development. In this study, we report significant AIF downregulation in the majority of renal cell carcinomas (RCC). In a group of RCC specimens, 84% (43 out of 51) had AIF downregulation by immunohistochemistry stain. Additional 10 kidney tumors, including an oxyphilic adenoma, also had significant AIF downregulation by Northern blot analysis. The mechanisms of the AIF downregulation included both AIF deletion and its promoter methylation. Forced expression of AIF in RCC cell lines induced massive apoptosis. Further analysis revealed that AIF interacted with STK3, a known regulator of apoptosis, and enhanced its phosphorylation at Thr180. These results suggest that AIF downregulation is a common event in kidney tumor development. AIF loss may lead to decreased STK3 activity, defective apoptosis and malignant transformation.

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References

Lee K, Ohyama T, Yajima N, Tsubuki S, Yonehara S . MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation. J Biol Chem. 2001; 276(22):19276-85. DOI: 10.1074/jbc.M005109200. View

Skyrlas A, Hantschke M, Passa V, Gaitanis G, Malamou-Mitsi V, Bassukas I . Expression of apoptosis-inducing factor (AIF) in keratoacanthomas and squamous cell carcinomas of the skin. Exp Dermatol. 2011; 20(8):674-6. DOI: 10.1111/j.1600-0625.2011.01249.x. View

Kook S, Son Y, Chung S, Lee S, Kim J, Jeon Y . Caspase-independent death of human osteosarcoma cells by flavonoids is driven by p53-mediated mitochondrial stress and nuclear translocation of AIF and endonuclease G. Apoptosis. 2007; 12(7):1289-98. DOI: 10.1007/s10495-007-0056-x. View

Vahsen N, Cande C, Briere J, Benit P, Joza N, Larochette N . AIF deficiency compromises oxidative phosphorylation. EMBO J. 2004; 23(23):4679-89. PMC: 533047. DOI: 10.1038/sj.emboj.7600461. View

Cande C, Cohen I, Daugas E, Ravagnan L, Larochette N, Zamzami N . Apoptosis-inducing factor (AIF): a novel caspase-independent death effector released from mitochondria. Biochimie. 2002; 84(2-3):215-22. DOI: 10.1016/s0300-9084(02)01374-3. View

Susin S, Zamzami N, Larochette N, Dallaporta B, Marzo I, Brenner C . A cytofluorometric assay of nuclear apoptosis induced in a cell-free system: application to ceramide-induced apoptosis. Exp Cell Res. 1997; 236(2):397-403. DOI: 10.1006/excr.1997.3733. View

Daugas E, Susin S, Zamzami N, Ferri K, Irinopoulou T, Larochette N . Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J. 2000; 14(5):729-39. View

Ahn S, Cheung W, Hsu J, Diaz R, Smith M, Allis C . Sterile 20 kinase phosphorylates histone H2B at serine 10 during hydrogen peroxide-induced apoptosis in S. cerevisiae. Cell. 2005; 120(1):25-36. DOI: 10.1016/j.cell.2004.11.016. View

Wang S, Li Y, Han F, Hu J, Yue L, Yu Y . Identification and characterization of MARVELD1, a novel nuclear protein that is down-regulated in multiple cancers and silenced by DNA methylation. Cancer Lett. 2009; 282(1):77-86. DOI: 10.1016/j.canlet.2009.03.008. View

10.

Seth R, Yang C, Kaushal V, Shah S, Kaushal G . p53-dependent caspase-2 activation in mitochondrial release of apoptosis-inducing factor and its role in renal tubular epithelial cell injury. J Biol Chem. 2005; 280(35):31230-9. DOI: 10.1074/jbc.M503305200. View

11.

Ramsahoye B, Biniszkiewicz D, Lyko F, Clark V, Bird A, Jaenisch R . Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A. 2000; 97(10):5237-42. PMC: 25812. DOI: 10.1073/pnas.97.10.5237. View

12.

Pan D . The hippo signaling pathway in development and cancer. Dev Cell. 2010; 19(4):491-505. PMC: 3124840. DOI: 10.1016/j.devcel.2010.09.011. View

13.

Saucedo L, Edgar B . Filling out the Hippo pathway. Nat Rev Mol Cell Biol. 2007; 8(8):613-21. DOI: 10.1038/nrm2221. View

14.

Cheville J, Lohse C, Zincke H, Weaver A, Blute M . Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma. Am J Surg Pathol. 2003; 27(5):612-24. DOI: 10.1097/00000478-200305000-00005. View

15.

Yuste V, Moubarak R, Delettre C, Bras M, Sancho P, Robert N . Cysteine protease inhibition prevents mitochondrial apoptosis-inducing factor (AIF) release. Cell Death Differ. 2005; 12(11):1445-8. DOI: 10.1038/sj.cdd.4401687. View

16.

Cheung W, Ajiro K, Samejima K, Kloc M, Cheung P, Mizzen C . Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase. Cell. 2003; 113(4):507-17. DOI: 10.1016/s0092-8674(03)00355-6. View

17.

Baritaud M, Boujrad H, Lorenzo H, Krantic S, Susin S . Histone H2AX: The missing link in AIF-mediated caspase-independent programmed necrosis. Cell Cycle. 2010; 9(16):3166-73. DOI: 10.4161/cc.9.16.12887. View

18.

Klein J, Longo-Guess C, Rossmann M, Seburn K, Hurd R, Frankel W . The harlequin mouse mutation downregulates apoptosis-inducing factor. Nature. 2002; 419(6905):367-74. DOI: 10.1038/nature01034. View

19.

Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D . Global cancer statistics. CA Cancer J Clin. 2011; 61(2):69-90. DOI: 10.3322/caac.20107. View

20.

Zeng F, Tian Y, Shi S, Wu Q, Liu S, Zheng H . Identification of mouse MARVELD1 as a microtubule associated protein that inhibits cell cycle progression and migration. Mol Cells. 2011; 31(3):267-74. PMC: 3932696. DOI: 10.1007/s10059-011-0037-3. View