Protein phosphatase 2A regulatory subunit B56alpha associates with c-myc and negatively regulates c-myc accumulation.
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, B56alpha, that selectively associates with the N terminus of c-Myc. B56alpha directs intact PP2A holoenzymes to c-Myc, resulting in a dramatic reduction in c-Myc levels. Inhibition of PP2A-B56alpha holoenzymes, using small hairpin RNA to knock down B56alpha, 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.
Arnold
Hugh K
HK
Department of Molecular and Medical Genetics, Oregon Health & Sciences University, 3181 S.W. Sam Jackson Park Rd., L103A, Portland, Oregon 97239, USA.
Sears
Rosalie C
RC
D020134:Catalytic Domain; D015536:Down-Regulation / Q000235:genetics*; D020035:Holoenzymes / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054648:Protein Phosphatase 2; D011499:Protein Processing, Post-Translational; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D012694:Serine / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D014764:Viral Proteins / Q000378:metabolism
C121517:E4orf4 protein, adenovirus; D020035:Holoenzymes; D021122:Protein Subunits; D016271:Proto-Oncogene Proteins c-myc; D014764:Viral Proteins; D012694:Serine; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2