e-journal

Regulation of c-Myc Protein Abundance by a Protein Phosphatase 2A–Glycogen Synthase Kinase 3β–Negative Feedback Pathway

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Regulation of Myc protein abundance is critical for normal cell growth as evidenced by the fact that deregulated Myc expression is a hallmark of many cancers. One of several important mechanisms that control Myc levels involves its phosphorylation-dependent proteolysis. Previous studies have shown that phosphorylation of threonine 58 by glycogen synthase kinase 3β (GSK3β) within the conserved Myc Box I sequence results in binding by the ubiquitin ligase Fbw7-SCF complex, followed by ubiquitination and proteasome-mediated degradation of Myc. Here, we show that induction
of Myc in several cell types correlates with loss of the inhibitory serine 9 phosphorylation of GSK3β and its increased kinase activity. The Mycinduced decrease in serine 9 phosphorylation is blocked by okadaic acid, an inhibitor of protein phosphatase 2A (PP2A). We therefore examined components of PP2A complexes and found that, among the regulatory B56 subunits, only the promoter of the ppp2r5d gene, encoding the B56δ isoform, is directly bound and transcriptionally activated by Myc in an E-box–dependent manner. Furthermore, we find that B56δ associates with both GSK3β and Myc, resulting in phosphorylation of Myc threonine 58, the well-established signal for ubiquitination and degradation. Furthermore, overexpression, or siRNA-mediated knockdown, of B56δ respectively results in accelerated, or retarded, rates of Myc degradation. Together, our data indicate that Myc limits its own abundance through a negative feedback pathway involving PP2A and GSK3β.

Keywords Myc, PP2A, GSK3β, degradation, phosphorylation

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Informasi Detail

Judul Seri

Genes & Cancer

No. Panggil

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Penerbit

: SAGE Publications Ltd., 2012

Deskripsi Fisik

Genes & Cancer 3(1) 23– 36 © The Author(s) 2012

Bahasa

English

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Tipe Isi

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Tipe Media

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Tipe Pembawa

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Edisi

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Subjek

KESEHATAN

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