Abstract
Cancer develops and progresses often by inactivating p53. Here, we unveil nerve growth factor receptor (NGFR, p75NTR or CD271) as a novel p53 inactivator. p53 activates NGFR transcription, whereas NGFR inactivates p53 by promoting its MDM2-mediated ubiquitin-dependent proteolysis and by directly binding to its central DNA binding domain and preventing its DNA-binding activity. Inversely, NGFR ablation activates p53, consequently inducing apoptosis, attenuating survival, and reducing clonogenic capability of cancer cells, as well as sensitizing human cancer cells to chemotherapeutic agents that induce p53 and suppressing mouse xenograft tumor growth. NGFR is highly expressed in human glioblastomas, and its gene is often amplified in breast cancers with wild type p53. Altogether, our results demonstrate that cancers hijack NGFR as an oncogenic inhibitor of p53.
Highlights
Tumorigenesis is highly associated with inactivation of the tumor suppressor p53, as it is mutated in ~50% of all types of human cancers, and its functions are impaired through various mechanisms in the rest of human cancers (Levine and Oren, 2009). p53 executes its tumor suppressive function mainly by inducing the expression of a large number of genes involved in cell cycle control, senescence, apoptosis, ferroptosis, autophagy, and metabolism (Jiang et al, 2015; Kruiswijk et al, 2015)
Knockdown of p53 markedly reduced nerve growth factor receptor (NGFR) mRNA level (Figure 1H and I). These results demonstrate that anti-cancer drug-induced NGFR expression in the cells is p53dependent
We identified NGFR as a novel p53 inactivator that serves as an example of a previously unidentified oncoprotein that may allow tumorigenesis in lieu of wt p53
Summary
Tumorigenesis is highly associated with inactivation of the tumor suppressor p53, as it is mutated in ~50% of all types of human cancers, and its functions are impaired through various mechanisms in the rest of human cancers (Levine and Oren, 2009). p53 executes its tumor suppressive function mainly by inducing the expression of a large number of genes involved in cell cycle control, senescence, apoptosis, ferroptosis, autophagy, and metabolism (Jiang et al, 2015; Kruiswijk et al, 2015). One key monitor of p53 is MDM2 (HDM2 in human), an oncoprotein encoded by a p53 transcriptional target gene that is amplified or overexpressed in several human tumors (Fakharzadeh et al, 1991; Momand et al, 1992; Oliner et al, 1992, 1993; Wu et al, 1993). The ARF tumor suppressor directly associates with MDM2 and inhibits MDM2-mediated p53 ubiquitination and degradation upon oncogenic stress (Palmero et al, 1998; Zhang et al, 1998; Zindy et al, 1998). Several ribosomal proteins boost p53 activation by untying the MDM2-p53 loop in response to ribosomal or nucleolar stress (Zhang and Lu, 2009; Zhou et al, 2012, 2015a).
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