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FLASH GENE

Symbol

TP73

contributors: mct/npt/pgu - updated : 01-09-2021

HGNC name	tumor protein p73
HGNC id	12003

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	ICS50 immotile cilia syndrome 50
Location	1p36.33      Physical location : 3.569.128 - 3.650.467
Synonym name	p53-related protein
	p53-like transcription factor
Synonym symbol(s)	P73, TAP73, CILD47, TRP73

DNA

TYPE	locus Control Region
STRUCTURE	83.69 kb     14 Exon(s)

Genomic sequence alignment details
10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Binding site   silencer
text structure	regulatory fragment in the first intron exerting silencer activity mediated by ZEB

MAPPING

cloned

Y

linked

status

confirmed

Map	pter - CDC2L1 - D1Z2 - D1S243 - D1S94 - D1S468 /TP73 - D1S47 - D1S214 - D1S1615 - ENO1 - TNFRSF1B - cen
Authors	PMID: 9858816, PMID: 10343122
Text	[TP73 ]

RNA

TRANSCRIPTS	type	messenger

text

a truncated form lacking the N terminal transactivation domain, three alternatively spliced isoforms alpha, beta, gamma at least seven C-terminal isoforms that differ in their transcriptional activity and at least four alternatively spliced deltaN isoforms initiated at different ATG (Marqués-García 2009) two classes of isoforms TAp73 (tumor suppressor isoforms containing the transactivation domain) and deltaNp73 (oncogenic isoforms, truncated and lacking the transactivation domain) with opposing effects (PMID: 24730526)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_001126240 12 - 2822 NP_001119712 - 587 - 2018 29733853 also called deltaN p73 alpha deltaNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TP73 or TP53 to block their transcriptional activities NM_001126241 11 - 2728 NP_001119713 - 450 - 2018 29733853 also called deltaN p73 beta down-regulation of TERT promoter activity deltaNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TP73 or TP53 to block their transcriptional activities NM_001126242 11 - 2062 NP_001119714 - 426 - 2018 29733853 also called deltaN p73 gamma CGTHBA inhibits the transactivation activity of TAp73gamma deltaNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TP73 or TP53 to block their transcriptional activities NM_005427 14 - 2845 NP_005418 - 636 - 2018 29733853 also called delta TP73 TAP73 alpha, direct target of GATA1 share many target genes with TP53, inducing cell cycle arrest, apoptosis, and differentiation lacks the transactivation domain and starts with an alternative exon (exon 3') capable of regulating TP73 and TP53 function since it is able to block their transactivation activity and their ability to induce apoptosis NM_001204184 13 - 5060 NP_001191113 - 499 - 2018 29733853 TAp73 beta NM_001204185 13 - 5005 NP_001191114 - 475 - 2018 29733853 TAp73 gamma NM_001204186 11 - 4772 NP_001191115 - 403 - 2018 29733853 TAp73 delta NM_001204187 12 - 4911 NP_001191116 - 555 - 2018 29733853 TAp73 epsilon NM_001204188 12 - 4904 NP_001191117 - 540 - 2018 29733853 TAp73 zeta NM_001204189 9 - 4749 NP_001191118 - 354 - 2018 29733853 delta NP73 delta deltaNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TP73 or TP53 to block their transcriptional activities NM_001204190 10 - 4888 NP_001191119 - 506 - 2018 29733853 deltaN p73 epsilon deltaNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TP73 or TP53 to block their transcriptional activities NM_001204191 10 - 4843 NP_001191120 - 491 - 2018 29733853 deltaN p73 zeta deltaNp73 isoforms lack the N-terminus transactivation domain; hence, cannot induce the expression of pro-apoptotic genes, but still can oligomerize with TP73 or TP53 to block their transcriptional activities NM_001204192 12 - 4964 NP_001191121 - 565 - 2018 29733853

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive mouth           salivary gland         Respiratory respiratory tract trachea

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal     Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

cell lineage

cell lines

fluid/secretion

at STAGE

IMPRINTING
text	biallelically expressed, except in fetal brain

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	N-terminal transactivation domain with strong homology to the core DNA binding region of TP53
	DNA binding and tetramerization domains
	C-terminal SAM domains, sterile alpha motif, SAMp73, involved in lipid binding and it is thought to mediate in protein-protein interactions

HOMOLOGY

intraspecies

homolog to TP53

Homologene

FAMILY

TP53 family

CATEGORY

transcription factor , tumor suppressor

SUBCELLULAR LOCALIZATION	plasma membrane,junction
	intracellular
	intracellular,cytoplasm,organelle,Golgi
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	activating transcription of TP53-responsive genes and inhibiting cell growth by inducing apoptosis
	putatively involved in neurogenesis sensory pathways and homeostatic control judging from TP73-deficient mice
	with ZNF143 and its target genes, involved in DNA repair gene expression and cisplatin resistance
	displaying a tumor suppressor activity similar to TP53
	regulator of SAC responses and TP73 loss can lead to mitotic arrest defects
	play a role in erythroid differentiation and may have a physiological role in developmental erythropoiesis
	role for TP73 and CKAP4 in supporting cellular proliferation through the transcriptional activation of the genes involved in G(1)-S and G(2)-M progression
	has a role in macrophage polarization and innate immunity, enhancing the action field of this important regulatory molecule
	plays a critical role in tumor suppression and neural development
	is a critical downstream mediator of HDAC1-regulated cell migration
	mutual regulation between TP73 and TRIM32 constitutes a novel feedback loop, which might have important implications in central nervous system development as well as relevance in oncogenesis
	has a unique role in spermatogenesis that ensures the maintenance of mitotic cells and normal spermiogenesis
	TP73 is essential for germ cell adhesion and maturation in testis
	can induce cell cycle arrest or apoptosis by the activation of TP53-responsive genes as well as TP53-independent pathways
	TP73 was required for TP53 stabilization and accumulation under AMPK activation, but was dispensable under DNA damage
	function as a tumor suppressor and regulates genomic integrity, cellular proliferation, and apoptosis
	is a novel central regulator of Motile multiciliated cells (MCCs) differentiation
	in addition to its role in the female germ line, TP73 regulates cell-cell contacts between developing sperm cells and supporting somatic cells in the male germ line
	participates in the control of angiogenesis in development and cancer
	mlticiliated cells (MCC) differentiation program is initiated by GMNC and MCIDAS, that activate key transcription factors, including TP73 and FOXJ1, to control the multiciliogenesis program

CELLULAR PROCESS

nucleotide, transcription

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

YAP1-TP73 signaling as a mechanism for cancer cell resistance to chemotherapies

a component

RANBP9/TP73 complex implicated in mitochondria-mediated apoptosis in addition to its role in enhancing APP generation

INTERACTION

DNA	DNA binding

RNA

small molecule

protein	directly interacts with Sp1, suggesting that formation of a TP73-Sp1 complex is the underlying mechanism for TP73-triggered inhibition of TERT expression
	interacting with SHISA5 (induces ER stress via the direct transactivation of Scotin)
	interacting with ZNF143
	interacting with HCK (HCK-SH3 domain-mediated interactions play an important role in the inhibition of TP73-dependent transcriptional activation of a target gene, NLRC4, as well as apoptosis)
	interact directly with several partners of the SAC, spindle assembly checkpoint, complex (BUB1, BUB3, and BUB1B)(involved in SAC protein localization and activities)
	role for MSH5 in DNA damage response involving ABL and TP73, suggesting that mutations impairing this process could significantly affect normal cellular responses to anti-cancer treatments
	interacts with CGTHBA (can modulate differentially the specific activities of selected TP73 isoforms)
	TP73 is a direct regulator for FOXJ1, a transcription factor important for the transactivation of genes encoding proteins involved in multiciliated cells (MCCs) differentiation
	TP73 binds to CASP8AP2 and is part of the complex that regulates histone gene transcription
	ubiquitination of TP73 mediated by RCHY1 represents an important pathway for controlling the suppressive function of TP73
	RBM38 is a target of TP73, the mutual regulation between TP73 and RBM38 constitutes a novel feed-forward loop, which might be explored as a target for tumors without a functional TP53
	important role of deregulated E2F in activation of the TP73 gene, a component of major intrinsic tumor suppressor pathways
	RANBP9 and TP73 have cooperative roles in inducing cell death, and the RANBP9/TP73 complex is implicated in mitochondria-mediated apoptosis in addition to its role in enhancing APP generation
	HDAC1 is a key regulator of TP73 protein stability
	TRIM32, a new direct TP73 transcriptional target in the context of neural progenitor cells, is differentially regulated by TP73
	TP73 regulates GLS2 during retinoic acid-induced terminal neuronal differentiation of neuroblastoma cells
	WWP2, an E3 ligase, is a novel TP73-associated protein that ubiquitinates and degrades TP73
	functional E3 ligase complex controlled by PPM1G that differentially regulates cellular TP73 and deltaNp73
	RPL11 and RPL5 activate TP73 by overcoming MDM2 inhibition
	TP73 directly activates the key regulators FOXJ1, RFX2, RFX3
	TP73 acts upstream of FOXJ1 and downstream of MCIDAS

cell & other

REGULATION

activated by

RPL11 and RPL5 that activate TP73 by overcoming MDM2 inhibition

induced by

E2F1 for apoptosis

Other

regulation of TP73 by the Cullin4A (cul4A)-dependent ligase (CDL4A) E3 complex, through the inhibition of its transcriptional function

ASSOCIATED DISORDERS

corresponding disease(s)

ICS50

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in bladder carcinoma tumoral   deletion     in neuroblastoma in advanced stage tumoral   amplification     in neuroblastoma,primary sqamous, primary sqamous cell carcinoma of the lung, head and neck cancer cell line tumoral   LOH     in hepatocellular carcinoma tumoral       loss of function by abnormal methylation or LOH in non-Hodgkin lymphoma tumoral     --low   correlates with increases of SAC protein expression in patients with lung cancer tumoral     --low gain of function loss of TAp73 or deltaNp73 up-regulation activates the angiogenic switch that stimulates tumor growth and progression tumoral     --low   TP73 methylation is common in patients with myelodysplastic syndromes and is associated with poor prognosis tumoral     --over   in cervical cancer tissues and cells

Susceptibility

to cancer

Variant & Polymorphism SNP	polymorphism (G4C14-A4T14) probably associates with cancer risk

Candidate gene
Marker	acts as a credible biomarker for predicting favorable overall survival in cervical cancer patients
Therapy target

ANIMAL & CELL MODELS

	Tp73 is a transcriptional activator of Ngfr and Ngfr mRNA and protein levels are strongly reduced in the central and peripheral nervous systems of p73 knockout mice
	Trp73-deficient mice have been reported to exhibit upper and lower airway infections due to a mucociliary clearance disorder