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Articles 1 - 5 of 5

Full-Text Articles in Biochemistry, Biophysics, and Structural Biology

Phosphorylation Of The Mdm2 Oncoprotein By The C-Abl Tyrosine Kinase Regulates P53 Tumor Suppression And The Radiosensitivity Of Mice, Michael I. Carr, Justine E. Roderick, Hong Zhang, Bruce A. Woda, Michelle A. Kelliher, Stephen N. Jones Dec 2016

Phosphorylation Of The Mdm2 Oncoprotein By The C-Abl Tyrosine Kinase Regulates P53 Tumor Suppression And The Radiosensitivity Of Mice, Michael I. Carr, Justine E. Roderick, Hong Zhang, Bruce A. Woda, Michelle A. Kelliher, Stephen N. Jones

UMass Metabolic Network Publications

The p53 tumor suppressor acts as a guardian of the genome by preventing the propagation of DNA damage-induced breaks and mutations to subsequent generations of cells. We have previously shown that phosphorylation of the Mdm2 oncoprotein at Ser394 by the ATM kinase is required for robust p53 stabilization and activation in cells treated with ionizing radiation, and that loss of Mdm2 Ser394 phosphorylation leads to spontaneous tumorigenesis and radioresistance in Mdm2S394A mice. Previous in vitro data indicate that the c-Abl kinase phosphorylates Mdm2 at the neighboring residue (Tyr393) in response to DNA damage to regulate p53-dependent apoptosis. In this present ...


The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan May 2016

The Roles Of Malt1 In Nf-Κb Activation And Solid Tumor Progression, Deng Pan

UT GSBS Dissertations and Theses (Open Access)

The transcription factor NF-κB plays a central role in many aspects of biological processes and diseases, such as inflammation and cancer. Although it has been suggested thatNF-κB is critical in tumorigenesis and tumor progression, the molecular mechanism by which NF-κB is activated in solid tumor remains largely unknown. In the current work, we focus on growth factor receptor-induced NF-κB activation and tumor progression, including epidermal growth factor receptor (EGFR)-induced NF-κB in lung cancer and heregulin receptor (HER2)-induced NF-κB in breast cancer. We found that Mucosa-associated lymphoma translocation protein 1 (MALT1), also known as paracaspase, is required for EGFR-induced ...


F-Box Protein Fbxo31 Directs Degradation Of Mdm2 To Facilitate P53-Mediated Growth Arrest Following Genotoxic Stress, Sunil K. Malonia, Parul Dutta, Manas Kumar Santra, Michael R. Green Jul 2015

F-Box Protein Fbxo31 Directs Degradation Of Mdm2 To Facilitate P53-Mediated Growth Arrest Following Genotoxic Stress, Sunil K. Malonia, Parul Dutta, Manas Kumar Santra, Michael R. Green

Molecular, Cell and Cancer Biology Publications

The tumor suppressor p53 plays a critical role in maintaining genomic stability. In response to genotoxic stress, p53 levels increase and induce cell-cycle arrest, senescence, or apoptosis, thereby preventing replication of damaged DNA. In unstressed cells, p53 is maintained at a low level. The major negative regulator of p53 is MDM2, an E3 ubiquitin ligase that directly interacts with p53 and promotes its polyubiquitination, leading to the subsequent destruction of p53 by the 26S proteasome. Following DNA damage, MDM2 is degraded rapidly, resulting in increased p53 stability. Because of the important role of MDM2 in modulating p53 function, it is ...


Fancm And Faap24 Maintain Genomic Stability Through Cooperative And Unique Functions, Yucai Wang Dec 2012

Fancm And Faap24 Maintain Genomic Stability Through Cooperative And Unique Functions, Yucai Wang

UT GSBS Dissertations and Theses (Open Access)

Fanconi anemia (FA) is a rare recessive genetic disease with an array of clinical manifestations including multiple congenital abnormalities, progressive bone marrow failure and profound cancer susceptibility. A hallmark of cells derived from FA patients is hypersensitivity to DNA interstrand crosslinking agents such as mitomycin C (MMC) and cisplatin, suggesting that FA- and FA-associated proteins play important roles in protecting cells from DNA interstrand crosslink (ICL) damage. Two genes involved in the FA pathway, FANCM and FAAP24, are of particular interest because they contain DNA interacting domains. However, there are no definitive patient mutations for these two genes, and the ...


Mechanism Of Cyclin D1-Dependent Genomic Instability And Neoplastic Transformation, Laura Pontano Vaites Aug 2011

Mechanism Of Cyclin D1-Dependent Genomic Instability And Neoplastic Transformation, Laura Pontano Vaites

Publicly Accessible Penn Dissertations

Regulation of cyclin D1-dependent kinase activity is essential for cell cycle progression and DNA replication fidelity. Critically, impaired cyclin D1 phosphorylation and ubiquitin-mediated proteolysis following the G1/S transition drives neoplastic growth, suggesting that posttranslational regulation is required for cell homeostasis. Elucidation of mechanisms facilitating S-phase cyclin D1 accumulation and novel functions of nuclear cyclin D1/CDK4 kinase is critical for understanding the role of cyclin D1 in tumorigenesis. The work presented herein demonstrates that accelerated, Fbx4-dependent cyclin D1 degradation following S-phase DNA damage is essential to maintain genome stability. Furthermore, Fbx4 functions as a bona fide tumor suppressor, as ...