Abstract
Both p53-related p63 and c-Myc are transcription factors playing key roles in cell proliferation, survival, development and tumorigenesis. In the present study, we identified that MM1, a c-Myc inhibitor, specifically binds to C-termini of p63β (including ΔNp63β and TAp63β). Further study demonstrates that p63β facilitates MM1 protein degradation via proteasomal pathway, resulting in elevation of c-Myc transactivation activity. Knockdown of ΔNp63β leads to decrease in c-Myc protein levels, concomitant with reduced expression of CDK4 and Cyclin D1, and impaired cell cycle progression, both of which are effectively reversed by simultaneous knockdown of MM1. Moreover, expression of p63 and CDK4 is concomitantly up-regulated in B-cell acute lymphoblastic leukemia. Together, this study reveals a novel crosstalk between p63 and c-Myc that may play an important role in cell cycle progression and tumorigenesis.
Highlights
TP63, known as the p63 gene, is a member of the p53 family, which locates on human chromosome 3q27–29 [1, 2]
Knockdown of ΔNp63a leads to decrease in c-Myc protein levels, concomitant with reduced expression of cyclin-dependent kinase 4 (CDK4) and Cyclin D1, and impaired cell cycle progression, both of which are effectively reversed by simultaneous knockdown of MM1
Since MM1 was previously reported to inhibit c-Myc, which is involved in cell cycle regulation, similar biological function that p63α possesses, we focused on MM1 and p63α in this study
Summary
TP63, known as the p63 gene, is a member of the p53 family, which locates on human chromosome 3q27–29 [1, 2]. Due to usage of alternative promoters, the p63 gene encodes two major classes of protein isoforms, TAp63 and ΔNp63. TAp63 proteins contain a full-length transactivation domain (TAD) at their N-termini that is homologous to that of p53, whereas ΔNp63 proteins possess incomplete N-terminal TADs. Owing to alternative splicing at the C-termini, TA or ΔN class of p63 can generate at least five different isoforms, including α, β, γ, δ, and ε [3]. Studies have shown that p63 proteins can function as transcription factors, controlling transcription of downstream genes, including p21, Bax, Puma, Dicer, MKP3, and genes involved in cell adhesion [5]. C-Myc is an important transcription factor involved in cell proliferation, survival, differentiation and tumorigenesis. We report that p63α physically interacts with and destabilizes MM1, resulting in elevation of c-Myc transactivation activity
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