Disease relevance of REPIN1

• Polyomavirus origin-dependent plasmid replication assays show RIP60 has weak replication enhancer activity, suggesting that RIP60 does not harbor a transcriptional transactivation domain [1].
• Furthermore, compared with that in normal fetal brain, the expression of AP4 and geminin is reduced in Down's syndrome fetal brain at 20 weeks of gestation age, at which time premature overexpression of dual-specificity tyrosine-phosphorylated and regulated kinase 1A (DYRK1A) is observed [2].
• Light-evoked responses of bipolar, amacrine, and ganglion cells associated with the On pathway were attenuated by L-AP5 in a manner similar to its lower-order homolog L-2-amino-4-phosphonobutyrate (AP4); nevertheless, L-AP5 was not an effective NMDA antagonist [3].
• On the basis of these results we conclude that AP-4 is a good candidate of cellular factors involved in BLV Tax trans activation [4].
• The rank order of potency to produce catalepsy was AP7 greater than D-AP5 greater than D,L-AP5 greater than cis-PDA greater than ASP-AMP greater than AP4 greater than L-AP5 greater than GAMS; there was a strong positive correlation between this rank order of potency in vivo and the potency order of these compounds in vitro as NMDA antagonists [5].

High impact information on REPIN1

• Replication initiator protein of plasmid R6K autoregulates its own synthesis at the transcriptional step [6].
• These include an AT-rich element, a 4-bp sequence located within the mapped IR, a region of intrinsically bent DNA located between these two elements, and a RIP60 protein binding site adjacent to the bent region [7].
• Replication of the Chinese hamster dihydrofolate (dhfr) gene initiates near a 281-bp HaeIII fragment of stably bent DNA that binds RIP60, a 60-kDa origin-specific DNA-binding protein that has been purified from HeLa cell nuclear extract (L. Dailey, M. S. Caddle, N. Heintz, and N. H. Heintz, Mol. Cell. Biol. 10:6225-6235, 1990) [8].
• RIP60, a mammalian origin-binding protein, enhances DNA bending near the dihydrofolate reductase origin of replication [8].
• L-AP4 inhibits calcium currents and synaptic transmission via a G-protein-coupled glutamate receptor [9].

Chemical compound and disease context of REPIN1

• The EAA antagonist AP4 (1 and 10 mg/kg) also reduced myoclonic jerks, but other drugs, such as the selective glycine antagonist Iso-THAO (1 and 10 mg/kg), strychnine (0.5 mg/kg), clonazepam, and diazepam (1 mg/kg), were ineffective blockers [10].

Biological context of REPIN1

• Because vertebrate origins of replication have no known consensus sequence, we suggest that sequence-specific DNA binding proteins such as RIP60 may act as accessory factors in origin identification prior to the assembly of pre-initiation complexes [1].
• The dhfr oribeta-binding protein RIP60 contains 15 zinc fingers: DNA binding and looping by the central three fingers and an associated proline-rich region [1].
• We examined the action of L-AP4 on voltage-dependent calcium currents and excitatory synaptic transmission on cultured olfactory bulb neurons using whole-cell voltage-clamp methods [9].
• Dialysis with staurosporine or buffering of intracellular calcium to pCa less than 8 did not block the action of L-AP4, suggesting that protein phosphorylation or release of intracellular calcium stores was not involved in calcium current inhibition under these experimental conditions [9].
• We have recently demonstrated that amino acid region 323-331 of factor Va heavy chain (9 amino acids, AP4') contains a binding site for factor Xa (Kalafatis, M., and Beck, D. O. (2002) Biochemistry 41, 12715-12728) [11].

Anatomical context of REPIN1

• The results obtained in vitro with AP4, kynurenic acid, and amino acid uptake inhibitors were confirmed in vivo by bathing segments of the rat spinal cord in situ with solutions containing antagonists and uptake inhibitors [12].
• The promoter activity was obviously influenced by AP1/AP4 (-375/-369nt) mutation in these three cell lines [13].
• With a multibarreled pipette for simultaneous ejection of drug and recording, iontophoresis of APV or CNQX into the red nucleus blocked bursting whereas AP4 failed to show a significant effect [14].
• Histological analyses demonstrated the same localization and developmental expression of beta-galactosidase and BAI1-AP4 in most neurons of the cerebral cortex and hippocampus [15].
• Here, the cellular response to cerebral application of L(+)-2-amino-4-phosphonobutanoic acid (AP4) was investigated in the CA1 region and dentate gyrus of freely moving rats [16].

Associations of REPIN1 with chemical compounds

• DNA bending directed by elements B1 to B5, as assessed by anomolous migration of DNA fragments on polyacrylamide gels, was accentuated at 4 degrees C. Bend element B5, which is in inverse orientation relative to elements B1 to B4, overlaps an ATT-rich motif that comprises the RIP60 protein-binding site [8].
• The AP4 (2-amino-4-phosphonobutyrate) receptor is a presynaptic glutamate receptor that inhibits transmitter release via an unknown mechanism [9].
• The present results suggest that an important component of the neurotransmission of bulbospinal respiratory drive involves endogenous excitatory amino acids acting at AP4-sensitive sites and other non-NMDA (quisqualate/kainate) receptors [12].
• Nevertheless, our results suggest that the racemic mixture of AP5 should not be used as an NMDA antagonist in retinal research, due to the AP4-like actions of its L-enantiomer [3].
• In contrast to previous reports, highly purified adenosine tetraphosphate (AP4) does not induce the aggregation of platelets but inhibits the aggregation and release reaction in platelet-rich plasma promoted by ADP [17].

Other interactions of REPIN1

• Previously we have shown that GST-Z2, a protein that contains three zinc fingers and a proline-rich multimerization domain from the polydactyl zinc finger protein RIP60 fused to glutathione S-transferase (GST), mediates DNA binding and looping in vitro [18].

Analytical, diagnostic and therapeutic context of REPIN1

• Gel mobility shift assays with circularly permuted bent DNA fragments and purified RIP60 showed that RIP60 markedly enhanced DNA bending of the dhfr origin region sequences [8].
• These observations parallel the compacted, interwound superhelices viewed by cryo-electron microscopy in vitrified solutions containing magnesium ions, and provide structural evidence in agreement with that from conventional EM for superhelical tension in RIP60 loop DNA [19].
• Northern blot analyses showed a unique pattern of beta-galactosidase expression in TG brain, peaking at 1 month after birth, like endogenous BAI1-AP4 [15].
• Sequence analysis, mutagenesis, and gel shift studies revealed a binding of AP4 and HIF-1 to the promoter, which affects the promoter activity [20].

References