Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple copies in T-cell maligancy (MCT-1) is a putative oncogene initially identified in a human T-cell lymphoma. Forced expression of MCT-1 has recently been shown to induce cell transformation and proliferation, as well as to activate survival-related PI-3K/AKT pathways protecting cells from apoptosis. MCT-1 protein is stabilized in response to DNA damage. The impact of MCT-1 overexpression on DNA damage response remains unknown. Here, we show that MCT-1 deregulates cell cycle checkpoints. The phosphorylation of genomic stabilizers H2AX and NBS1 are enhanced in MCT-1-overexpressing cells. Forced expression of MCT-1 significantly increases the number of DNA damage-induced foci involving gamma-H2AX and 53BP1. In MCT-1-overexpressing cells, the proportion of S-phase cell population is preferentially increased after exposure to gamma-irradiation compared to controls. Knockdown of endogenous MCT-1 using an siRNA approach attenuates the H2AX phosphorylation and the G1/S checkpoint defect. Furthermore, MCT-1 is capable of transforming immortalized human mammary epithelial cells and promoting genomic instability. These data shed light on the role of MCT-1 in the cellular response to DNA damage and its involvement in malignant transformation.
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PMID:The MCT-1 oncogene product impairs cell cycle checkpoint control and transforms human mammary epithelial cells. 1589 92

Wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may have a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossed Atm-deficient mice to Wip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes. Atm null mice, like ATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared with Atm null mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared with their Atm null counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared with Atm null mice. Finally, doubly null mice were partially rescued from gametogenesis defects observed in Atm null mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular.
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PMID:Absence of Wip1 partially rescues Atm deficiency phenotypes in mice. 2176 65