Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following the induction of DNA damage, a prominent route of cell inactivation is apoptosis. During the last ten years, specific DNA lesions that trigger apoptosis have been identified. These include O6-methylguanine, base N-alkylations, bulky DNA adducts, DNA cross-links and DNA double-strand breaks (DSBs). Repair of these lesions are important in preventing apoptosis. An exception is O6-methylguanine-thymine lesions, which require mismatch repair for triggering apoptosis. Apoptosis induced by many chemical genotoxins is the consequence of blockage of DNA replication, which leads to collapse of replication forks and DSB formation. These DSBs are thought to be crucial downstream apoptosis-triggering lesions. DSBs are detected by ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) proteins, which signal downstream to CHK1, CHK2 (checkpoint kinases) and p53. p53 induces transcriptional activation of pro-apoptotic factors such as FAS, PUMA and BAX. Many tumors harbor mutations in p53. There are p53 backup systems that involve CHK1 and/or CHK2-driven E2F1 activation and p73 upregulation, which in turn transcribes BAX, PUMA and NOXA. Another trigger of apoptosis upon DNA damage is the inhibition of RNA synthesis, which leads to a decline in the level of critical gene products such as MKP1 (mitogen-activated protein kinase phosphatase). This causes sustained activation of JNK (Jun kinase) and, finally, AP-1, which stimulates death-receptor activation. DNA damage-triggered signaling and execution of apoptosis is cell-type- and genotoxin-specific depending on the p53 (p63 and p73) status, death-receptor responsiveness, MAP-kinase activation and, most importantly, DNA repair capacity. Because most clinical anti-cancer drugs target DNA, increasing knowledge on DNA damage-triggered signaling leading to cell death is expected to provide new strategies for therapeutic interventions.
 ...
PMID:DNA damage-induced cell death by apoptosis. 1689 8

The nuclear transcription factor E2F1 plays an important role in modulating neuronal death in response to excitotoxicity and cerebral ischemia. Here, by comparing gene expression in brain cortices from E2F1(+/+) and E2F1(-/-) mice using a custom high-density DNA microarray, we identified a group of putative E2F1 target genes that might be responsible for ischemia-induced E2F1-dependent neuronal death. Neuropilin 1 (NRP-1), a receptor for semaphorin 3A-mediated axon growth cone collapse and retraction, was confirmed to be a direct target of E2F1 based on (i) the fact that the NRP-1 promoter sequence contains an E2F1 binding site, (ii) reactivation of NRP-1 expression in E2F1(-/-) neurons when the E2F1 gene was replaced, (iii) activation of the NRP-1 promoter by E2F1 in a luciferase reporter assay, (iv) electrophoretic mobility gel shift analysis confirmation of the presence of an E2F binding sequence in the NRP-1 promoter, and (v) the fact that a chromatin immunoprecipitation assay showed that E2F1 binds directly to the endogenous NRP-1 promoter. Interestingly, the temporal induction in cerebral ischemia-induced E2F1 binding to the NRP-1 promoter correlated with the temporal-induction profile of NRP-1 mRNA, confirming that E2F1 positively regulates NRP-1 during cerebral ischemia. Functional analysis also showed that NRP-1 receptor expression was extremely low in E2F1(-/-) neurons, which led to the diminished response to semaphorin 3A-induced axonal shortening and neuronal death. An NRP-1 selective peptide inhibitor provided neuroprotection against oxygen-glucose deprivation. Taken together, these findings support a model in which E2F1 targets NRP-1 to modulate axonal damage and neuronal death in response to cerebral ischemia.
 ...
PMID:Neuropilin-1 is a direct target of the transcription factor E2F1 during cerebral ischemia-induced neuronal death in vivo. 1717 35

E2F transcription factors regulate the progression of the cell cycle by repression or transactivation of genes that encode cyclins, cyclin dependent kinases, checkpoint regulators, and replication proteins. Although some E2F functions are independent of the Retinoblastoma tumor suppressor (Rb) and related family members, p107 and p130, much of E2F-mediated repression of S phase entry is dependent upon Rb. We previously showed in cultured mouse embryonic fibroblasts that concomitant loss of three E2F activators with overlapping functions (E2F1, E2F2, and E2F3) triggered the p53-p21(Cip1) response and caused cell cycle arrest. Here we report on a dramatic difference in the requirement for E2F during development and in cultured cells by showing that cell cycle entry occurs normally in E2f1-3 triply-deficient epithelial stem cells and progenitors of the developing lens. Sixteen days after birth, however, massive apoptosis in differentiating epithelium leads to a collapse of the entire eye. Prior to this collapse, we find that expression of cell cycle-regulated genes in E2F-deficient lenses is aberrantly high. In a second set of experiments, we demonstrate that E2F3 ablation alone does not cause abnormalities in lens development but rescues phenotypic defects caused by loss of Rb, a binding partner of E2F known to recruit histone deacetylases, SWI/SNF and CtBP-polycomb complexes, methyltransferases, and other co-repressors to gene promoters. Together, these data implicate E2F1-3 in mediating transcriptional repression by Rb during cell cycle exit and point to a critical role for their repressive functions in cell survival.
 ...
PMID:Cell proliferation in the absence of E2F1-3. 2118 83

Collapsin response mediator proteins (CRMPs) are ubiquitously expressed in neurons from worms to humans. A cardinal feature of CRMPs is to mediate growth cone collapse in response to Semaphorin-3A signaling through interactions with cytoskeletal proteins. These are critical regulatory roles that CRMPs play during neuritogenesis and neural network formation. Through post-translational modifications, such as phosphorylation, O-GlcNAcylation, SUMOylation, and proteolytic cleavage, CRMPs participate in synaptic plasticity by modulating NMDA receptors, L- and N-type voltage-gated calcium channels (VGCCs), thus affecting neurotransmitter release. CRMPs also possess histone deacetylase (HDAC) activity, which deacetylates histone H4 during neuronal death. Calcium-dependent proteolytic cleavage of CRMPs results in the truncation of CRMPs, producing a large 54 kD fragment (p54). Translocation of the p54 fragment into the nucleus leads to deacetylation of nuclear histone H4 and de-repression of transcription factor E2F1 expression. Increased expression of E2F1 elevates the expression of genes in cell cycle and death. These new and exciting studies lead to the realization that CRMPs are multifunctional proteins with both regulatory and enzymatic functions. Increasing numbers of studies associate these functions of CRMPs with the development of mental and neurological disorders, such as schizophrenia, Alzheimer's diseases, brain trauma, and stroke. This review focuses on new evidence showing the regulatory and enzymatic functions of CRMPs and highlights recent understandings of CRMPs' roles in neurological diseases.
 ...
PMID:The regulatory and enzymatic functions of CRMPs in neuritogenesis, synaptic plasticity, and gene transcription. 3265 66