Koji Itahana

Research Interests:

Our overall research goal in fighting against cancers is to gain a better understanding of apoptotic cell death and cancer metabolism in order to develop novel therapeutic strategies. We will accomplish this goal using biochemical analysis and mouse models. Our research is based on my recent findings related to the tumor suppressor ARF and its role in mediating mitochondrial signaling pathways.

One of the focuses in our laboratory is the apoptotic function of ARF in vivo. Previous reports have indicated that ARF-null mice are tumor prone and that ARF induces either apoptosis or cell cycle arrest depending on the cellular context. However, which of these functions of ARF is important for tumor suppression in specific tissues is largely unknown. Understanding which defect in tumor suppression occurs in certain cancer types will potentially lead to the development of mechanism-based therapeutic strategies against these cancers. Based on my previous work, we will generate apoptosis-deficient ARF knock-in mice possessing mutations found in human cancers in order to dissect the apoptotic function of ARF in vivo.

The second focus of our laboratory is the role of ARF in cancer metabolism. One aspect of cancer's lethal nature stems from its resistance to apoptosis induced by chemotherapy and radiotherapy; however, the underlying mechanisms are largely unknown. It is well known that cancers have a unique metabolic profile with a high mitochondrial membrane potential that might confer apoptosis resistance and therefore be therapeutically targeted. I have recently reported that when ARF translocates to the mitochondria, it can reduce mitochondrial membrane potential and sensitize cancer cells to apoptosis. Understanding the mechanism by which ARF reduces the mitochondrial membrane potential and regulates cancer cell metabolism may provide novel mitochondrial therapeutic targets for these highly apoptosis-resistant cancers.

Finally, our third project will study the role of an ARF-binding partner, the mitochondrial protein p32, in mitochondria. I have recently shown that p32 is critical for ARF-mediated apoptosis and is required for ARF to localize in mitochondria. Although p32 is exclusively localized in mitochondria, its mitochondrial function is poorly understood. We will investigate the role of p32 in mitochondrial physiology, metabolism, and apoptosis to improve our understanding of mitochondrial signaling pathways mediated by ARF.

We will take these three approaches to gain a better understanding of the molecular mechanisms involved in cancer development. We believe these studies will contribute to the development of much-needed novel therapeutic strategies for this complex, heterogeneous, and extremely fatal disease.

Selected Publications:

Huang M, Itahana K, Zhang Y, Mitchell BS (2009) Depletion of guanine nucleotides leads to the Mdm2-dependent proteasomal degradation of nucleostemin. Cancer Res. 69:7:3004-3012

Itahana K, Clegg HV, Zhang Y (2008) ARF in the mitochondria: the last frontier? Cell Cycle 7:23:3641-3646 (Review)

Itahana K and Zhang Y (2008) Mitochondrial p32 is a critical mediator of ARF-induced apoptosis. Cancer Cell 13(6):542-553 (featured article)

Itahana K, Mao H, Jin A, Itahana Y, Clegg H, Lindström MS, Bhat K, Godfrey VL, Evan GI, Zhang Y (2007) Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 12:4:355-366 (cover article, comment in Nature Reviews Cancer 2007, 7(12), 896)

Jin A, Itahana K, O'Keefe K, Zhang Y (2004) Inhibition of HDM2 and activation of p53 by ribosomal protein L23. Mol Cell Biol. 24:17:7669-7680

Bhat KP, Itahana K, Jin A, Zhang Y (2004) Essential role of ribosomal protein L11 in mediating growth inhibition-induced p53 activation. EMBO J. 23:12:2402-2412

Itahana K, Campisi J, Dimri GP (2004) Mechanisms of cellular senescence in human and mouse cells. Biogerontology 5:1:1-10 (Review)

Itahana K, Bhat KP, Jin A, Itahana Y, Hawke D, Kobayashi R, Zhang Y (2003) Tumor suppressor ARF degrades B23, a nucleolar protein involved in ribosome biogenesis and cell proliferation. Mol Cell. 12:5:1151-1164

Itahana K, Zou Y, Itahana Y, Martinez JL, Beausejour C, Jacobs JJ, Van Lohuizen M, Band V, Campisi J, Dimri GP (2003) Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1. Mol Cell Biol. 23:1:389-401

Itahana K, Dimri GP, Hara E, Itahana Y, Zou Y, Desprez PY, Campisi J. (2002) A role for p53 in maintaining and establishing the quiescence growth arrest in human cells. J Biol Chem. 277:20:18206-18214