Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial dysautonomia (FD) is a neurodevelopmental genetic disorder within the larger classification of hereditary sensory and autonomic neuropathies, each caused by a different genetic error. The FD gene has been identified as IKBKAP. Mutations result in tissue-specific expression of mutant IkappaB kinase-associated protein (IKAP). The genetic error probably affects development, as well as maintenance, of neurons because there is neuropathological and clinical progression. Pathological alterations consist of decreased unmyelinated and small-fiber neurons. Clinical features reflect widespread involvement of sensory and autonomic neurons. Sensory loss includes impaired pain and temperature appreciation. Autonomic features include dysphagia, vomiting crises, blood pressure lability, and sudomotor dysfunction. Central dysfunction includes emotional lability and ataxia. With supportive treatment, prognosis has improved greatly. About 40% of patients are over age 20 years. The cause of death is usually pulmonary failure, unexplained sudden deaths, or renal failure. With the discovery of the genetic defect, definitive treatments are anticipated.
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PMID:Familial dysautonomia. 1498 33

Nuclear factor kappaB (NF-kappaB) has been implicated in inducible chemoresistance against anthracyclines. In an effort to improve the cytotoxicity of anthracyclines while reducing their cardiotoxic effects, we have developed a novel class of extranuclear-localizing 14-O-acylanthracyclines that bind to the phorbol ester/diacylglycerol-binding C1b domain of conventional and novel protein kinase C (PKC) isoforms, thereby promoting an apoptotic response. Because PKCs have been shown to be involved in NF-kappaB activation, in this report, we determined the mechanism of NF-kappaB activation by N-benzyladriamycin-14-valerate (AD 198) and N-benzyladriamycin-14-pivalate (AD 445), two novel 14-O-acylanthracylines. We show that the induction of NF-kappaB activity in response to drug treatment relies on the activation of PKC-delta and NF-kappaB-activating kinase (NAK), independent of ataxia telengectasia mutated and p53 activities. In turn, NAK activates the IKK complex through phosphorylation of the IKK-2 subunit. We find that neither NF-kappaB activation nor ectopic expression of Bcl-X(L) confers protection from AD 198-induced cell killing. Overall, our data indicate that activation of novel PKC isoforms by cytoplasmic-targeted 14-O-acylanthracyclines promotes an apoptotic response independent of DNA damage, which is unimpeded by inducible activation of NF-kappaB.
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PMID:Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines. 1504 34

Upon genotoxic stresses, cells activate IkappaB kinases (IKKs) and the transcription factor NF-kappaB to modulate apoptotic responses. The SUMO-1 ligase PIASy and the kinase ataxia talengiectasia mutated (ATM) have been implicated to SUMOylate and phosphorylate nuclear IKKgamma (NEMO) in a consecutive mode of action, which in turn results in activation of cytoplasmic IKK holocomplexes. However, the nuclear signals and scaffold structures that initiate IKKgamma recruitment and activation are unknown. Here, we show that poly(ADP-ribose)-polymerase-1 (PARP-1) is the DNA proximal regulator, which senses DNA strand breaks and, through poly(ADP-ribose) (PAR) synthesis, assembles IKKgamma, PIASy, and ATM in a dynamic manner. Signalosome formation involves direct protein-protein interactions and binding to ADP-ribose polymers through PAR binding motifs (PARBM). Activated PARP-1 and a PARBM in PIASy are required to trigger IKKgamma SUMOylation, which in turn permits IKK and NF-kappaB activation, as well as NF-kappaB-regulated resistance to apoptosis.
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PMID:A nuclear poly(ADP-ribose)-dependent signalosome confers DNA damage-induced IkappaB kinase activation. 1991 42