Disease relevance of TIPARP

• It has been reported that an uncharacterized gene, corresponding to a 5'-truncated partial cDNA DKFZp434J214, is amplified and up-regulated together with CCNL in head-and-neck squamous cell carcinoma (HNSCC) [1].
• At the scene of ischemic brain injury: is PARP a perp [2]?
• These findings reveal a novel mechanism linking demyelination and progressive neuronal damage, which might represent an underlying insidious process driving disease beyond a primary white matter phenomenon and rendering the microglial PARP-1 a possible antiinflammatory therapeutic target [3].
• The 46 kDa DBD of human PARP, and several derivatives thereof mutated in its first or second zinc-finger, were overproduced in Escherichia coli, in CV-1 monkey cells or in human fibroblasts to study their DNA-binding properties, the trans-dominant inhibition of resident PARP activity, and the consequences on DNA repair, respectively [4].
• In a rat model of hypoglycemic brain injury, neuronal PARP-1 activation and subsequent neuronal death were blocked by the ERK1/2 inhibitor 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) [5].

High impact information on TIPARP

• When neurons are stimulated by membrane depolarization, calcium signaling mediated by CaMKII induces dissociation of KIF4 from PARP-1, resulting in upregulation of PARP-1 activity, which supports neuron survival [6].
• The C-terminal domain of KIF4 is a module that suppresses the activity of poly (ADP-ribose) polymerase-1 (PARP-1), a nuclear enzyme known to maintain cell homeostasis by repairing DNA and serving as a transcriptional regulator [6].
• After dissociation from PARP-1, KIF4 enters into the cytoplasm from the nucleus and moves to the distal part of neurites in a microtubule-dependent manner [6].
• PARP-1, an enzyme that catalyzes the attachment of ADP ribose units to target proteins, plays at least two important roles in transcription regulation [7].
• Second, PARP-1 acts as a component of enhancer/promoter regulatory complexes [7].

Chemical compound and disease context of TIPARP

• To elucidate causes of apoptotic defects, we studied the protein expression of Apaf-1, procaspases-2, -3, -6, -7, -8, -10, and poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) in cells from children with acute lymphoblastic leukemia (ALL; n = 43) and acute myeloid leukemia (AML; n = 10) [8].
• In the present report, we supplement our preliminary observations and demonstrate in 2 murine and 2 human melanoma cell lines that lovastatin effectively potentiates the cytostatic/cytotoxic activity of doxorubicin in vitro via an augmentation of apoptosis (estimated with PARP-cleavage assay, annexin V assay and TUNEL) [9].
• Inhibitors of poly(ADP-ribose)polymerase (PARP; EC 2.4.2.30), such as 3-aminobenzamide (3-AB), can be used to assess the role of the enzyme in the induction of DNA lesions in euploid cells as compared to cells of genetic conditions known to exhibit increased susceptibility to chemical or physical mutagens, such as Down's syndrome (DS) lymphocytes [10].
• We previously demonstrated that intravenous or intra-cerebral administration of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors increases the antitumor activity of temozolomide (TMZ), an oral anticancer drug used for the treatment of malignant melanoma and primary or secondary brain tumors [11].
• In this study, we investigated the biological effects and the molecular mechanisms of two structurally unrelated selective inhibitors of PARP-1, 3-aminobenzamide (3-AB) and 1,5-dihydroxyisoquinoline (-DIQ), in an in vivo model of myocardial ischemia and reperfusion [12].

Biological context of TIPARP

• Identification and characterization of human TIPARP gene within the CCNL amplicon at human chromosome 3q25.31 [1].
• Fugu tiparp gene was located around nucleotide position 14280-23355 of fugu genome draft sequence CAAB01003597 [1].
• Complete coding sequence of human TIPARP mRNA was determined in silico by assembling nucleotide sequences of BC034397 and DKFZp434J214 cDNAs [1].
• Here, we identified that the novel gene, corresponding to the 5'-truncated DKFZp434J214 cDNA, is the human ortholog of mouse Tiparp gene, by using bioinformatics [1].
• In contrast, hyperoxia, an activator of PARP, is associated with accelerated telomere loss, activation of p53 and premature senescence [13].

Anatomical context of TIPARP

• FCCP induced apoptotic cell death in both cell lines in a dose-dependent manner, and we were able to demonstrate an appearance of caspase-3-dependent PARP cleavage fragments with Western blot and the appearance of large (15-50 kb) DNA fragments using pulsed-field gel electrophoresis [14].
• NCS-induced phosphorylation of histone H2AX on serine 139 in Parp-1(-/-) embryonic stem cell (ES) clones was also higher than that in Parp-1(+/+) ES clone [15].
• IL-6-differentiated B cells die by apoptosis, as evidenced by increases in Annexin V binding activity, PARP cleavage, and chromatin disorganization [16].
• The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) triggers a cell-death pathway in which mitochondria play an integral part, but it remains uncertain how PARP-1 activation in the nucleus is signaled to the mitochondria [17].
• Resultant SSRI-induced apoptosis was preceded by caspase activation, poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, DNA fragmentation, a loss of mitochondrial membrane potential, and the externalization of phosphatidylserine, and reversed by the overexpression of bcl-2 [18].

Associations of TIPARP with chemical compounds

• CONCLUSIONS: In living cells, ANI is about 1000-fold more potent at inhibiting PARP activity compared with 3-aminobenzamide (3-ABA) [19].
• It was shown by biochemical fractionation procedure that PARP-1 as well as ATM increases at chromatin level after induction of DSB with neocarzinostatin (NCS) [15].
• Upon binding to DNA breaks, activated PARP cleaves NAD(+) into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors, and PARP itself [20].
• A positive correlation was found between the in vitro DNA-binding capacity of the recombinant DBD polypeptides and their inhibitory effect on PARP activity stimulated by the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) [4].
• In this paper we show, by metabolic labelling with [3H]fatty acids, that the PARP anchor contains palmitate esterified to inositol, and stearate at sn-1, in a monoacylglycerol moiety, a structure identical to PP1 [21].

Other interactions of TIPARP

• Human TIPARP showed 27.5% and 26.0% total-amino-acid identity with human FLJ22693 and ZAP, respectively [1].

Analytical, diagnostic and therapeutic context of TIPARP

• Because inhibitors of PARP are able to potentiate the cell-killing effects of some DNA-damaging agents and to inhibit the repair of induced DNA strand breaks, such compounds may enhance the anti-tumour efficacy of radiotherapy or cytotoxic drug treatment [19].
• Inhibitors of PARP-1 activity in combination with DNA-binding antitumor drugs may constitute a suitable strategy in cancer chemotherapy [22].
• Furthermore, intranasal administration of IL-5 restored the impairment of eosinophil recruitment and mucus production in OVA-challenged PARP-1(-/-) mice [23].
• Since caspase-8, -3 and -7 were not activated and PARP was not cleaved in these cells as judged by western blotting and immunofluorescence studies, it is likely that this is an atypical form of programmed cell death owing to a proteinase(s) independent of caspases [24].
• Gel retardation assay indicates that PARP augments DNA binding activity of E2 in vitro [25].

References