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Molecular and Cellular Biology, April 2006, p. 2832-2844, Vol. 26, No. 7
0270-7306/06/$08.00+0 doi:10.1128/MCB.26.7.2832-2844.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Protein Phosphatase 2A Regulatory Subunit B56
Associates with c-Myc and Negatively Regulates c-Myc Accumulation
Hugh K. Arnold and
Rosalie C. Sears*
Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, Oregon 97239
Received 22 August 2005/
Returned for modification 7 October 2005/
Accepted 10 January 2006
Protein phosphatase 2A (PP2A) plays a prominent role in controlling accumulation of the proto-oncoprotein c-Myc. PP2A mediates its effects on c-Myc by dephosphorylating a conserved residue that normally stabilizes c-Myc, and in this way, PP2A enhances c-Myc ubiquitin-mediated degradation. Stringent regulation of c-Myc levels is essential for normal cell function, as c-Myc overexpression can lead to cell transformation. Conversely, PP2A has tumor suppressor activity. Uncovering relevant PP2A holoenzymes for a particular target has been limited by the fact that cellular PP2A represents a large heterogeneous population of trimeric holoenzymes, composed of a conserved catalytic subunit and a structural subunit along with a variable regulatory subunit which directs the holoenzyme to a specific target. We now report the identification of a specific PP2A regulatory subunit, B56
, that selectively associates with the N terminus of c-Myc. B56
directs intact PP2A holoenzymes to c-Myc, resulting in a dramatic reduction in c-Myc levels. Inhibition of PP2A-B56
holoenzymes, using small hairpin RNA to knock down B56
, results in c-Myc overexpression, elevated levels of c-Myc serine 62 phosphorylation, and increased c-Myc function. These results uncover a new protein involved in regulating c-Myc expression and reveal a critical interconnection between a potent oncoprotein, c-Myc, and a well-documented tumor suppressor, PP2A.
* Corresponding author. Mailing address: Department of Molecular and Medical Genetics, Oregon Health & Sciences University, 3181 S.W. Sam Jackson Park Rd., L103A, Portland, OR 97239. Phone: (503) 494-6885. Fax: (503) 494-4411. E-mail:
searsr{at}ohsu.edu.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, April 2006, p. 2832-2844, Vol. 26, No. 7
0022-538X/06/$08.00+0 doi:10.1128/MCB.26.7.2832-2844.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
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