Directory

The primary goal of our laboratory is to develop novel therapeutic strategies by investigating ARF-MDM2-p53 tumor suppressive mechanisms, cancer metabolism, and stem cell biology.

Revealing Non-Canonical Functions of the ARF-MDM2-p53 Pathway 
The ARF-MDM2-p53 pathway is a well-known tumor suppressive pathway that needs to be abrogated for cells to become cancerous. My postdoctoral research projects have focused on this pathway, uncovering new functions of ARF such as inhibiting ribosome biogenesis by degrading NPM1 (Mol Cell, 2003) and inducing apoptosis via p32 in mitochondria (Cancer Cell, 2008), in addition to studying the regulation of MDM2 degradation in vivo (Cancer Cell, 2007). Interestingly, recent mouse models have revisited the long-held view of canonical functions of the ARF-MDM2-p53 pathway, highlighting the importance of its non-canonical and diverse roles. Yet, little is known about these new functions of p53, their mediators, and how they contribute to tumor suppression and tissue homeostasis. Therefore, our laboratory is committed to uncovering these novel non-canonical functions. We have demonstrated a novel role of ARF in preventing genomic instability caused by centrosome amplification (MCB 2015) and activating immune response by inhibiting PIAS1 via SUMOylation (J Immunol 2018). Furthermore, we revealed unique epigenetic strategies in human embryonic stem cells (hESCs) that control p53 target gene expression (Sci Rep 2016), and new roles for p53 in response to histone methylation inhibitors (Clin Cancer Res, 2012) and to irradiation in quiescent cells (BBRC 2015), as well as the role of BCAR1 in mutant p53-mediated cancer cell invasion (Br J Cancer 2020). Our other ongoing research projects also include the mechanism of the p53 pathway in hESCs, stem cell maintenance, and tissue homeostasis.

Revealing a Potential Strategy Targeting Cancer Metabolism
The second focus of our laboratory is studying cancer metabolism. It is well established that cancers have unique metabolic profiles that may promote cancer development and cause chemotherapy resistance. These unique metabolic properties can be therapeutically targeted. We have demonstrated the first beneficial link between p53 and uric acid for an antioxidant function to prevent cancer (Oncogene 2015) and identified that the p53-TGM2 pathway acts as a critical barrier to prevent oncogenic transformation by promoting autophagy (eLife 2016). We also elucidated the novel role of PP2A (Sci Signal 2018) and AMPK (J Cell Sci 2022) in glucose metabolism in cancer. We also uncovered the important role of ABCB1 in superior tumor suppression and longevity in bats (Nat Commun 2019). Our ongoing research projects also include studying metabolic regulation in hESCs, hematopoietic stem cells, and senescent cells, as well as tissue homeostasis using organoids as a model.

Exploring bat-inspired cyclic tryptophan diketopiperazines as ABCB1 Inhibitors.
Koh JYP*, Itahana Y*, Krah A*, Mostafa H*, Ong MM, Iwamura S, Vincent DM, Krishnan SR, Ye W, Yim PWC, Khopade TM, Chen K, Kong PS, Wang LF, Bates RW, Kimura Y, Viswanathan R**, Bond PJ**, Itahana K** (in press)
Commun Chem.  (*equal contribution) (**co-corresponding authors)

Multi-omic analysis of bat versus human fibroblasts reveals altered central metabolism.
Jagannathan NS*, Koh JYP*, Lee Y, Sobota RM, Irving A, Wang LF, Itahana Y**, Itahana K**, Tucker-Kellogg L** (in press)
eLife (*equal contribution) (**co-corresponding authors)

"The 10th International MDM2 Workshop": Opening up new avenues for MDM2 and p53 research, the First International MDM2 Workshop in Asia.
Ohki R*, Itahana K*, Iwakuma T* (2024)
Genes Cells. Online ahead of print. (review) (*equal contribution) 

Redox-dependent AMPK inactivation disrupts metabolic adaptation to glucose starvation in xCT-overexpressing cancer cells.
Lee Y, Itahana Y, Ong CC, Itahana K (2022)
J Cell Sci. 135:15:jcs259090

Mutant TP53 interacts with BCAR1 to contribute to cancer cell invasion.
Guo AK, Itahana Y, Seshachalam VP, Chow HY, Ghosh S, Itahana K (2021)
Br J Cancer. 124:1:299-312

Potassium channel dysfunction in human neuronal models of Angelman syndrome.
Sun AX, Yuan Q, Fukuda M, Yu W, Yan H, Lim GGY, Nai MH, D'Agostino GA, Tran HD, Itahana Y, Wang D, Lokman H, Itahana K, Lim SWL, Tang J, Chang YY, Zhang M, Cook SA, Rackham OJL, Lim CT, Tan EK, Ng HH, Lim KL, Jiang YH, Je HS (2019)
Science. 366:6472:1486-1492

Koh J, Itahana Y, Mendenhall IH, Low D, Soh EXY, Guo AK, Chionh YT, Wang LF*, Itahana K* (2019)
Nat Commun. 10:1:2820 (*co-corresponding authors)

High basal heat-shock protein expression in bats confers resistance to cellular heat/oxidative stress.
Chionh YT, Cui J, Koh J, Mendenhall IH, Ng JHJ, Low D, Itahana K, Irving AT, Wang LF (2019)
Cell Stress Chaperones. 24:4:835-849

Tumor suppressor p14ARF enhances IFNγ-activated immune response by inhibiting PIAS1 via SUMOylation.
Alagu J, Itahana Y, Sim F, Chao SH, Bi X, Itahana K (2018)
J Immunol. pii: ji1800327

Ca2+-dependent PP2Ac demethylation promotes cancer cell death in response to glucose deprivation independently of inhibiting glycolysis.
Lee HY, Itahana Y, Schuechner S, Fukuda M, Je HS, Ogris E, Virshup DM, Itahana K (2018)
Sci Signal. 11:512, pii: eaam7893

Emerging Roles of p53 Family Members in Glucose Metabolism.
Itahana Y, Itahana K (2018)
Int J Mol Sci. 19:3, pii: E776 (review)

p32 regulates ER stress and lipid homeostasis by down-regulating GCS1 expression.
Liu Y, Leslie PL, Jin A, Itahana K, Graves LM, Zhang Y (2018)
FASEB J. fj201701004RR

p32 heterozygosity protects against age- and diet-induced obesity by increasing energy expenditure.
Liu Y, Leslie PL, Jin A, Itahana K, Graves LM, Zhang Y (2017)
Sci Rep.18:7:1:5754.

Histone modifications and p53 binding poise the p21 promoter for activation in human embryonic stem cells.
Itahana Y*, Zhang J*, Göke J, Vardy LA, Han R, Iwamoto K, Engin C, Robson P, Pouladi MA, Colman A**,Itahana K** (2016)
Sci Rep. 6:28112 (*equal contribution) (**co-corresponding authors)

Germline hemizygous deletion of CDKN2A-CDKN2B locus in a patient presenting with Li-Fraumeni syndrome.
Chan SH, Lim WK, Michalski S, Lim JQ, Ishak ND, Met-Domestici M, Ng CCY, Vikstrom K, Esplin ED, Fulbright J, Ang MK, Wee J, Sittampalam K, Farid M, Lincoln SE, Itahana K, Abdullah S, Teh BT, Ngeow J (2016)
npj Genomic Medicine. 1:16015

Transglutaminase 2 (TGM2) contributes to a p53-induced autophagy program to prevent oncogenic transformation.  
Yeo SY*, Itahana Y*, Guo AK, Han R, Iwamoto K, Nguyen TH, Bao Y, Kleiber K, Wu YJ, Bay BH, Voorhoeve PM**, Itahana K** (2016)
eLife. 5:e07101 (*equal contribution) (**co-corresponding authors) 

TRIM28 is an E3 ligase for ARF-mediated NPM1/B23 SUMOylation that represses centrosome amplification. 
Neo SH*, Itahana Y*, Alagu J, Kitagawa M, Guo A, Lee SH, Tang K, Itahana K (2015)
Mol Cell Biol. 35:16:2851-2863 (*equal contribution)

Quiescence does not affect p53 and stress response by irradiation in human lung fibroblasts.
Dai J, Itahana K*, Baskar R* (2015) 
Biochem Biophys Res Commun. 458:1:104-109 (*co-corresponding authors)

The uric acid transporter SLC2A9 is a direct target gene of the tumor suppressor p53 contributing to antioxidant defense.
Itahana Y, Han R, Barbier S, Lei Z, Rozen S, Itahana K (2015) 
Oncogene. 34:14:1799-1810

Colorimetric detection of senescence-associated β galactosidase.
Itahana K, Itahana Y, Dimri GP. (2013) 
Methods Mol Biol. 965:143-156

TP53 genomic status regulates sensitivity of gastric cancer cells to the histone methylation inhibitor 3-Deazaneplanocin A (DZNep)
Cheng LL, Itahana Y, Lei ZD, Chia NY, Wu Y, Yu Y, Zhang SL, Thike AA, Pandey A, Rozen S, Voorhoeve PM, Yu Q, Tan PH, Bay BH, Itahana K*, Tan P* (2012). 
Clin Cancer Res. 18:15:4201-4212 (*co-corresponding authors)

Emerging roles of mitochondrial p53 and ARF.
Itahana Y, Itahana K (2012) 
Curr Drug Targets. 13:13:1633-1640 (Review)

The diverse and complex roles of radiation on cancer treatment: therapeutic target and genome maintenance.
Baskar R, Yap SP, Chua KL, Itahana K (2012) 
Am J Cancer Res. 2:4:372-382 (Review)

Mdm2 RING mutation enhances p53 transcriptional activity and p53-p300 interaction.
Clegg HV, Itahana Y, Itahana K, Ramalingam S, Zhang Y (2012) 
PLoS One. 7:5:e38212

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

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

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

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

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

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