The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

Figures & data

Table 1. Connections between miRNAs and the p53 family.

miRNA	Connection with the p53 family	Reference
let-7d	oncogenic miRNA processed via the ΔNp63/DGCR8 axis	[41]
miR-17-5p	oncogenic miRNA repressed by p53	[122]
miR-34a	p53 induced miRNA mediating cell cycle arrest and senescence	[117,121]
miR-106b	oncogenic miRNA repressed by p53	[122]
miR-128	oncogenic miRNA processed via the ΔNp63/DGCR8 axis	[41]
miR-130b	tumour suppressive miRNA repressed by ΔNp63 and induced by TAp63	[43,123]
miR-155	oncogenic miRNA repressed by p53	[122]
miR-181	tumour suppressive miRNA suppressed by ΔNp63	[123]
miR-193b	miRNA induced by TAp73 and binding to the 3ʹ UTR of p73	[129]
miR-200	induced by ΔNp63 to regulate EMT	[125]
miR-203	tumour suppressive miRNA binding the 3ʹ UTR of p63	[131]
miR-205	induced by ΔNp63 to regulate EMT and mammary gland development	[125,126]
miR-630	pro-proliferative miRNA induced by ΔNp63	[124]

Table 2. Connections between lncRNAs and the p53 family.

lncRNA	Connection with the p53 family	Reference
ANRIL	oncogenic lncRNA destabilizing p53 by repressing ARF	[141]
BLNCR	direct ΔNp63 target promoting cancer cell proliferation	[158]
DINO	interacts with p53 and promotes p53-mediated cell cycle arrest	[154]
GUARDIN	direct p53 target involved in DNA repair	[155]
MALAT1	promotes p53 deacetylation via SIRT1	[150]
PANDA	direct p53 target promoting senescence	[156]
PINCR	p53-induced lncRNA counteracting p53-dependent apoptosis	[153]
PURPL	direct p53 target inhibiting p53 stabilization	[152]
PVT1	oncogenic lncRNA destabilizing p53 by repressing LATS2	[147]
SNHG1	oncogenic lncRNA inhibiting TAp63’s anti-metastatic activity	[157]
WRAP53	promotes the translation of the p53 mRNA	[151]
XIAP-AS1	direct ΔNp63 target promoting cancer cell invasion	[159]

Table 3. Connections between circRNAs and the p53 family.

circRNA	Connection with the p53 family	Reference
circ_0000263	destabilizes p53 via miR-150-5p/MDM4	[171]
circ_0055538	tumour suppressor required for p53-dependent apoptosis	[172]
circAMOTL1L	tumour suppressor mediating p53 suppression of EMT	[173]
circANRIL	causes p53 activation via nucleolar stress	[170]
PINT	p53 target encoding a small tumour suppressive peptide	[169]

Figure 1. The p53 family modulates the nucleolar stress response. Nucleolar structure and function are impaired by multiple stressors, including inhibitors of ribosomal DNA transcription such as CX-5461 and hernandonine. These compounds induce p53 stabilization, which relies on its interaction with PML and subsequent p300-mediated acetylation. Once activated, p53 counteracts the ΔNp63-induced transcription of ribosomal genes and prompts cell death in concert with the other pro-apoptotic members of the family, TAp63 and TAp73.

Figure 2. TAp73 controls global protein synthesis via the translation of ribosomal proteins. In physiological conditions, TAp73 promotes the translation of mRNAs encoding ribosomal proteins (RPs), which in turn are required to sustain global protein synthesis. When nucleolar stress occurs, instead, TAp73 forestalls the production of RPs thus ultimately halting global protein synthesis.

Figure 3. miR-34a inhibits the tRNA initiator tRNA^Met. Following either endogenous (e.g. oncogene activation) or exogenous (e.g. DNA damaging agents) stimuli, p53 is activated and promotes the expression of miR-34a, which is the only miRNA known to target tRNAs. Specifically, miR-34a binds to tRNA^Met and prevents it from promoting biological processes supporting tumour formation and progression.

Figure 4. The p53 family regulates multiple layers of the miRNA biogenesis pathway. In addition to directly regulating the expression of miRNAs (see Table 1), p53 and its family members, TAp63 and ΔNp63, affect miRNA processing as well as the activity of miRNAs on their mRNA targets.

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