Abstract
The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.
Highlights
The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression
While c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19 ARF in mouse) that binds to and inhibits the E3 ubiquitin–protein ligase mouse double minute 2 homolog (MDM2) leading to p53 activation[10,11], p53 transcriptionally inactivates c-Myc and represses c-Myc through microRNAmediated mechanisms[12,13]
Results c-Myc drives Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP) expression that is upregulated in diverse cancer types
Summary
- Flag-c-Myc - GAPDH suggesting that despite their close proximity, c-Myc selectively transactivates MILIP but not MAFG. Overexpression of MILIP promoted, albeit moderately, clonogenicity of A549 and MCF-7 cells, whereas cessation of induced MILIP silencing led to recovery of the growth of A549 xenografts along with MILIP expression (Fig. 2b, Supplementary Fig. 6e–g). Silencing of MILIP decelerated anchorage-independent growth of HME-1 caused by c-Myc overexpression in conjunction with knockdown of p14ARF (Fig. 2f, Supplementary Fig. 8e, f). Overexpression of MILIP increased p53 polyubiquitination and reduced its expression (Supplementary Fig. 9c, d) This reduction in p53 expression was abolished by the addition of the proteasomal inhibitor MG132 (Supplementary Fig. 9d), confirming that MILIP inactivates p53 through promoting its polyubiquitination and subsequent proteasomal degradation. MILIP appeared to be an RNA binding partner of p53, as it physically associated with p53 in A549 and MCF-7 cells
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