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

Genotoxic treatments, such as UV light, camptothecin, and adozelesin, stall DNA replication and subsequently generate DNA strand breaks. Typically, DNA breaks are reflected by an increase in ataxia and Rad-related kinase (ATR)-regulated phosphorylation of H2AX (gammaH2AX) and require replication fork movement. This study examined the potential of the monofunctional DNA alkylating agent hedamycin, a powerful inhibitor of DNA replication, to induce DNA strand breaks, phosphorylated H2AX (gammaH2AX) foci, and chromosome aberrations. Hedamycin treatment of HCT116 carcinoma cells resulted in a rapid induction of DNA strand breaks accompanied by increasing H2AX phosphorylation and focalization. Unlike many other treatments that also stall replication, such as UV, camptothecin, and adozelesin, gammaH2AX formation was not suppressed in ATR-compromised cells but actually increased. Similarly, hedamycin induction of gammaH2AX is not dependent on ataxia telangiectasia mutated or DNA-protein kinase, and pretreatment of cells with the phosphatidylinositol 3-kinase-related kinase inhibitor caffeine did not substantially reduce induction of H2AX phosphorylation by hedamycin. Furthermore, the DNA replication inhibitor aphidicolin only modestly depressed hedamycin-induced gammaH2AX formation, indicating that hedamycin-induced DNA double-strand breaks are not dependent on fork progression. In contrast, camptothecin- and adozelesin-induced gammaH2AX was strongly suppressed by aphidicolin. Moreover, after 24 hours following a short-term hedamycin treatment, cells displayed high levels of breaks in interphase nuclear DNA and misjoined chromosomes in metaphase cells. Finally, focalization of a tightly bound form of Ku80 was observed in interphase cells, consistent with the subsequent appearance of chromosomal aberrations via abnormal nonhomologous end joining. Overall, this study has revealed a disparate type of DNA damage response to stalled replication induced by a bulky DNA adduct inducer, hedamycin, that seems not to be highly dependent on ATR or DNA replication.
 ...
PMID:Hedamycin, a DNA alkylator, induces (gamma)H2AX and chromosome aberrations: involvement of phosphatidylinositol 3-kinase-related kinases and DNA replication fork movement. 1609 33

The posterior parietal cortex (PPC) is essential for the integration of visuomotor information during visually guided reaching. Studies in macaque monkeys have demonstrated a functional specialisation around the intraparietal sulcus (IPS) with a more medial representation of hand movements ("parietal reach region") and a more lateral representation of saccadic eye movements (lateral intraparietal area, LIP). Here we present evidence for the validity of this concept with respect to the human parietal cortex. We recorded isolated and combined goal-directed eye-hand movements in normal control subjects and in a patient with bilateral parieto-occipital lesions and incomplete Balint's syndrome including severe optic ataxia (misreaching to visual targets). Brain lesions in the patient were caused by acute posterior leucoencephalopathy in association with aortic surgery because of Takayasu's arteritis. MRI scans showed bilateral line-shaped hemorrhagic lesions, restricted to the cortex at the medial banks of the intraparietal sulcus, but leaving its lateral banks largely intact. In the patient visually guided reaching was significantly dysmetric, whereas the metrics of visually guided saccades were within normal limits. Dysmetria was more pronounced for the right visual field, with a gross hypermetria. Variability of the movement improved when a delay of 5 or 10 s was introduced between target presentation and movement execution. Lesion data support the concept of a functional specialisation around the human IPS: The cortex medial to the IPS predominantly controls rapid goal-directed reaching movements, comparable to the parietal reach region in monkeys, whereas saccadic eye movements appear to be controlled rather by the cortex lateral to the IPS.
 ...
PMID:Functional dissociation of saccade and hand reaching control with bilateral lesions of the medial wall of the intraparietal sulcus: implications for optic ataxia. 1749 72

We report an unexpected role for Tel2 in the expression of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Although Tel2 was identified as a budding yeast gene required for the telomere length maintenance, we found no obvious telomeric function for mammalian Tel2. Targeted gene deletion showed that mouse Tel2 is essential in embryonic development, embryonic stem (ES) cells, and embryonic fibroblasts. Conditional deletion of Tel2 from embryonic fibroblasts compromised their response to IR and UV, diminishing the activation of checkpoint kinases and their downstream effectors. The effects of Tel2 deletion correlated with significantly reduced protein levels for the PI3K-related kinases ataxia telangiectasia mutated (ATM), ATM and Rad3 related (ATR), DNA-dependent protein kinase catalytic subunit ataxia (DNA-PKcs). Tel2 deletion also elicited specific depletion of the mammalian target of rapamycin (mTOR), suppressor with morphological effect on genitalia 1 (SMG1), and transformation/transcription domain-associated protein (TRRAP), and curbed mTOR signaling, indicating that Tel2 affects all six mammalian PIKKs. While Tel2 deletion did not alter PIKK mRNA levels, in vivo pulse labeling experiments showed that Tel2 controls the stability of ATM and mTOR. Each of the PIKK family members associated with Tel2 in vivo and in vitro experiments indicated that Tel2 binds to part of the HEAT repeat segments of ATM and mTOR. These data identify Tel2 as a highly conserved regulator of PIKK stability.
 ...
PMID:Tel2 regulates the stability of PI3K-related protein kinases. 1816 36