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Sci. Signal., 6 November 2012
Vol. 5, Issue 249, p. ra80
[DOI: 10.1126/scisignal.2003065]

RESEARCH ARTICLES

Proliferative and Antiapoptotic Signaling Stimulated by Nuclear-Localized PDK1 Results in Oncogenesis

Chintan K. Kikani1*, Erik V. Verona2, Jiyoon Ryu2, Yanying Shen3, Qingqing Ye4, Li Zheng4, Ziliang Qian4, Hiroshi Sakaue5, Kyoko Nakamura5, Jie Du6, Qunsheng Ji4, Wataru Ogawa5, Lu-Zhe Sun2, Lily Q. Dong2,7,8, and Feng Liu1,7,8{dagger}

1 Department of Biochemistry, University of Texas Health Science Center, San Antonio, TX 78229, USA.
2 Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
3 Department of Pathology, Shanghai Renji Hospital, Shanghai Jiaotong University, 1630 Dongfang Road, Shanghai 200127, China.
4 AstraZeneca Innovation Center of China, 898 Halei Road, Shanghai 201203, China.
5 Department of Clinical Molecular Medicine, Division of Diabetes and Digestive and Kidney Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
6 Beijing Anzhen Hospital Affiliated to the Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing 100029, China.
7 Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229, USA.
8 The Barshop Center for Longevity and Aging Studies, University of Texas Health Science Center, San Antonio, TX 78229, USA.

* Present address: Department of Biochemistry, University of Utah School of Medicine, University of Utah, 15 N Medical Drive East, Salt Lake City, UT 84112, USA.

Abstract: Enhanced activation of phosphoinositide 3-kinase (PI3K) is a hallmark of many human tumors because it promotes cell proliferation and survival through several mechanisms. One of these mechanisms is the phosphorylation of the serine and threonine kinase Akt at the cytosolic side of the plasma membrane by phosphoinositide-dependent protein kinase 1 (PDK1), which is recruited and activated by binding to the phosphoinositides produced by PI3K. We previously demonstrated increased nuclear accumulation of PDK1 in cells with enhanced PI3K activity. We report that nuclear PDK1 promoted cell proliferation by suppressing FOXO3A-dependent transcription of the gene encoding p27Kip1 (an inhibitor of cell cycle progression), whereas it enhanced cell survival by inhibiting the activation of c-Jun amino-terminal kinase. Cells with nuclear-localized PDK1 showed anchorage-independent growth, and when injected into mice, these cells induced the formation of solid tumors. In human prostate tumors, cytoplasmic localization of PDK1 correlated only with early-stage, low-risk tumors, whereas nuclear PDK1 localization correlated with high-risk tumors. Together, our findings suggest a role for nuclear-translocated PDK1 in oncogenic cellular transformation and tumor progression in mice and humans.

{dagger} To whom correspondence should be addressed. E-mail: liuf{at}uthscsa.edu

Citation: C. K. Kikani, E. V. Verona, J. Ryu, Y. Shen, Q. Ye, L. Zheng, Z. Qian, H. Sakaue, K. Nakamura, J. Du, Q. Ji, W. Ogawa, L.-Z. Sun, L. Q. Dong, F. Liu, Proliferative and Antiapoptotic Signaling Stimulated by Nuclear-Localized PDK1 Results in Oncogenesis. Sci. Signal. 5, ra80 (2012).

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