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Molecular and Cellular Biology, April 2006, p. 2947-2954, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.2947-2954.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Subcellular Targeting of p33ING1b by Phosphorylation-Dependent 14-3-3 Binding Regulates p21WAF1 Expression

Wei Gong, Michael Russell, Keiko Suzuki, and Karl Riabowol*

Southern Alberta Cancer Research Institute, Departments of Biochemistry, Molecular Biology, and Oncology, University of Calgary, Calgary, Alberta T2N 4N1, Canada

Received 7 September 2005/ Returned for modification 5 October 2005/ Accepted 30 December 2005

ING1 is a type II tumor suppressor that affects cell growth, stress signaling, apoptosis, and DNA repair by altering chromatin structure and regulating transcription. Decreased ING1 expression is seen in several human cancers, and mislocalization has been noted in diverse types of cancer cells. Aberrant targeting may, therefore, functionally inactivate ING1. Bioinformatics analysis identified a sequence between the nuclear localization sequence and plant homeodomain domains of ING1 that closely matched the binding motif of 14-3-3 proteins that target cargo proteins to specific subcellular locales. We find that the widely expressed p33ING1b splicing isoform of ING1 interacts with members of the 14-3-3 family of proteins and that this interaction is regulated by the phosphorylation status of ING1. 14-3-3 binding resulted in significant amounts of p33ING1b protein being tethered in the cytoplasm. As shown previously, ectopic expression of p33ING1b increased levels of the p21Waf1 cyclin-dependent kinase inhibitor upon UV-induced DNA damage. Overexpression of 14-3-3 inhibited the up-regulation of p21Waf1 by p33ING1b, consistent with the idea that mislocalization blocks at least one of ING1's biological activities. These data support the idea that the 14-3-3 proteins play a crucial role in regulating the activity of p33ING1b by directing its subcellular localization.

* Corresponding author. Mailing address: #370 Heritage Medical Research Building, 3330 Hospital Dr. NW, Calgary, AB T2N 4N1, Canada. Phone: (403) 220-8695. Fax: (403) 270-0834. E-mail: karl{at}ucalgary.ca.

Molecular and Cellular Biology, April 2006, p. 2947-2954, Vol. 26, No. 8
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.8.2947-2954.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Garate, M., Campos, E. I., Bush, J. A., Xiao, H., Li, G. (2007). Phosphorylation of the tumor suppressor p33ING1b at Ser-126 influences its protein stability and proliferation of melanoma cells. FASEB J. 21: 3705-3716 [Abstract] [Full Text]  
  • Wang, Y., Dai, D. L., Martinka, M., Li, G. (2007). Prognostic Significance of Nuclear ING3 Expression in Human Cutaneous Melanoma. Clin. Cancer Res. 13: 4111-4116 [Abstract] [Full Text]  


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