1,721,070 research outputs found
Control of APC-Cdc20 by the tumor suppressor RASSF1A
No full textThe tumor suppressor gene RASSF1A is frequently hypermethylated in various tumors. However, how RASSF1A functions in tumor suppression was unknown. Our study shows that RASSF1A regulates the stability of mitotic cyclins and the timing of mitotic progression by inhibiting APC-Cdc20. RASSF1A appears to work in early pro-metaphase, after Emi1 destruction and before activation of the Mad2-dependent spindle checkpoint. Loss of RASSF1A expression induces premature APC activation, thereby resulting in acceleration of mitotic cyclin degradation and mitotic progression as well as induction of mitotic abnormalities. Thus, RASSF1A plays a critical role in mitotic progression and tumor suppression by controlling APC-Cdc20 activity
The role of ATM in DNA damage responses and cancer
No full textAtaxia-telangiectasia (AT) is a complex, autosomal recessive disorder characterized by cerebellar ataxia, believed to result from progressive neurodegeneration, and telangiectasia, dilation of blood vessels within the eyes and parts of the facial region. AT patients suffer from recurrent infections caused by both cellular and humoral immune deficiencies and as a population, are significantly predisposed to cancer, particularly lymphomas and leukemias. Early attempts at treating these malignancies with radiotherapy revealed another hallmark of AT, a profound hypersensitivity to the cytotoxic effects of ionizing radiation (IR) which is recapitulated at the cellular level in culture. Predisposition to cancer and radiosensitivity observed in AT has been linked to chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage. These earlier observations predicted that the gene defective in AT may encode a protein which plays a crucial role in sensing DNA damage and transducing signals that promote cell survival. Through the combined efforts of linkage analysis and positional cloning, a single gene was identified on chromosome 11q22-33 by Shiloh and colleagues and was found to be mutated in all four complementation groups previously characterized in cell lines derived from AT patients (Savitsky et al,, 1995a,b), The predicted ATM gene product shows considerable homology to an emerging family of high molecular weight, phosphatidylinositol -3 kinase (PI-3 K)-related proteins involved in eukaryotic cell cycle control, DNA repair, and DNA recombination (Zakian, 1995), This landmark discovery has triggered a resurgence of biochemical and genetic studies focusing on ATM function which has brought forth insights regarding ATM activity and its role in DNA damage signaling
Dual role of Nbs1 in the ataxia telangiectasia mutated-dependent DNA damage response
No full textThe Nbs1 protein associates with Mre11 and Rad50 proteins to form the Mre11-Rad50-Nbs1 complex, which plays an important role in the intracellular signaling pathway activated in response to DNA damage. Mutations in the genes for each of these three components of the Mre11-Rad50-Nbs1 complex result in human diseases characterized by genomic instability. Insight into the functions of Nbs1 in the DNA damage response mediated by the protein kinase, ataxia telangiectasia mutated, has been provided by recent studies. Nbs1 acts both as a downstream target of ataxia telangiectasia mutated in the S-phase checkpoint of the cell cycle as well as an upstream modulator or activator of ataxia telangiectasia mutated in the DNA damage response.It was supported by the National Research
Laboratory Program and the 21st Century Frontier
Functional Human Genome Project of Korea
Insulin receptor substrate 2: a bridge between Hippo and AKT pathways
No full textNAFLD induces the development of advanced liver diseases such as NASH and liver cancer. Therefore, understanding the mechanism of NAFLD development is critical for its prevention and treatment Ablation of PTEN or Hippo pathway components induces liver cancer in a murine model by hyperactive AKT or YAP/TAZ, respectively. Although the regulation of these two pathways occurs in the same hepatocyte, the details of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver homeostasis and tumorigenesis still remain unclear. Here, we found that depletion of both PTEN and SAV1 in liver promotes spontaneous NAFLD and liver cancer through hyperactive AKT via YAP/TAZ-mediated up-regulation of IRS2 transcription. Conversely, NAFLD is rescued by both ablation of YAP/TAZ and activation of the Hippo pathway. Furthermore, human HCC patients with NAFLD showed strong correlation between YAP/TAZ and IRS2 or phospho-AKT expression. Finally, the inhibition of AKT by MK-2206 treatment attenuates NAFLD development and tumorigenesis. Our findings indicate that Hippo pathway interacts with AKT signaling during the intervention with IRS2 to prevent NAFLD and liver cancer.
Analysis of ataxia-telangiectasia mutated (ATM)- and Nijmegen breakage syndrome (NBS)-regulated gene expression patterns
No full textPurpose. Ataxia-telangiectasia (A-T) is a progressive, degenerative, complex autosomal recessive disease characterized by cerebellar degeneration, immunodeficiency, premature aging, radiosensitivity, and a predisposition to cancer. Mutations in the ataxia-telangiectasia mutated (atm) gene, which phosphorylates downstream effector proteins, are linked to A-T. One of the proteins phosphorylated by the ATM protein is Nijmegen Breakage Syndrome protein (NBS, p95/nibrin), which was recently shown to be encoded by a gene mutated in the Nijmegen breakage syndrome (nbs), an autosomal recessive disease with a phenotype virtually similar to that of A-T. The similarities in the clinical and cellular features of NBS and A-T have led us to hypothesize that the two corresponding gene products may function in similar ways in the cellular signaling pathway. Thus, we sought to identify genes whose expression is mediated by the atm and nbs gene products. Material and methods. To identify genes, we performed an analysis of oligonucleotide microarrays using the appropriate cell lines, isogenic A-T (ATM(-)) and control cells (ATM(+)), and isogenic NBS (NBS-) and control cells (NBS+). Results. We examined genes regulated by ATM and NBS, respectively. To determine the effect of ATM and NBS on gene expression in detail, we classified these genes into different functional categories, including those involved in apoptosis, cell cycle/DNA replication, growth/differentiation, signal transduction, cell-cell adhesion, and metabolism. In addition, we compared the genes regulated by the ATM and NBS to determine the relationship of their signaling pathways and to better understand their functional relationship. Conclusions. We found that, while ATM and NBS regulate several genes in common, both of these proteins also have distinct patterns of gene regulation, findings consistent with the functional overlap and distinctiveness of these two conditions. Due to the role of ATM and NBS in tumor suppression and the response to chemotherapy and radiotherapy, these findings may assist in the development of a more rational approach to cancer treatment, as well as a better understanding of tumorigenesis
The many substrates and functions of ATM
No full textAs its name suggests, the ATM - 'ataxia-telangiectasia, mutated' - gene is responsible for the rare disorder ataxia-telangiectasia. Patients show various abnormalities, mainly in their responses to DNA damage, but also in other cellular processes. Although it is hard to understand how a single gene product is involved in so many physiological processes, a clear picture is starting to emerge
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