The correlation between stress-induced nucleolar disruption and abrogation of p53 degradation is evident after a wide variety cellular stresses. This link may be caused by steps in regulation occurring nucleoli, as suggested some biochemical evidence. Alternatively, also causes redistribution proteins, potentially altering their interactions with and/or MDM2. raises the fundamental question whether nucleolus controls directly, i.e., site where regulatory processes occur, or indirectly,...

The MDM2 protein, through its interaction with p53, plays an important role in the regulation of G1 checkpoint cell cycle. In addition to binding and inhibiting transcriptional activation function p53 binds, inter alia, RB E2F-1·DP-1 complex so doing may promote progression cells into S phase. Mice transgenic for Mdm2 possess that have cycle defects develop altered tumor profile independent their status. also blocks growth inhibitory effects transforming factor-β1 a p53-independent manner....

Primary radiotherapy (RT) is a mainstay of treatment for laryngeal squamous cell carcinoma (LSCC). Although the cure rates early (T1) vocal cord tumours are high, RT proves ineffective in up to third T3 carcinomas. Moreover, associated with debilitating early- and late-treatment-related toxicity, thus finding means de-escalate therapy, while retaining/augmenting therapeutic effectiveness, highly desirable. p53 key mediator radiation responses; we therefore investigated whether Nutlin-3,...

Adjuvant fluoropyrimidine-based (5-FU) chemotherapy is a mainstay of treatment for colorectal cancer (CRC), but only provides benefit subset patients. To improve stratification we examined (for the first time in CRC), whether analysis GRP78 expression predictive biomarker and performed functional studies to examine role sensitivity 5-FU. 396 CRC patient samples were collected prospective uniform manner was determined by immunohistochemistry on tissue microarrays using well-validated...

p53 is a critical coordinator of wide range stress responses. To facilitate rapid response to stress, produced constitutively but negatively regulated by MDM2. MDM2 can inhibit in multiple independent ways: binding its transcription activation domain, inhibiting acetylation, promoting nuclear export, and probably most importantly proteasomal degradation p53. The latter achieved via MDM2's E3 ubiquitin ligase activity harbored within the RING finger domain. We have discovered that MTBP...

Loss of p53 function is a critical event in tumor evolution. This occurs through range molecular events, typically missense mutation followed by loss heterozygosity. In many cancers, there compelling evidence that cells can compromise have selective advantage. The situation renal cell carcinoma unclear. It has recently been suggested unusually compromised novel dominant, MDM2/p14ARF-independent mechanism. hard to reconcile with other recent studies identified as an important prognostic...

Abstract MDM2 is a ubiquitin ligase that best known for its essential function in the negative regulation of p53. In addition, expression associated with tumor progression number common cancers, and some cases, this has been shown to be independent p53 status. promote degradation other proteins involved normal cell growth proliferation, including MDM4 RB1. Here, we describe identification novel substrate ligase: dihydrofolate reductase (DHFR). binds directly DHFR catalyses monoubiquitination...

Hereditary pancreatitis (HP) is an autosomal dominant disease that displays the features of both acute and chronic pancreatitis. Mutations in human cationic trypsinogen (PRSS1) are associated with HP have provided some insight into pathogenesis pancreatitis, but mechanisms responsible for initiation not been elucidated role apoptosis necrosis has much debated. However, it generally accepted trypsinogen, prematurely activated within pancreatic acinar cell, a major process. Functional studies...

What's known on the subject? and What does study add? Unlike most other cancers mutations of p53 gene ( TP53 ), typically indicated by increased expression, are rare in renal cell carcinomas (RCC) there is no evidence that mutation associated with outcome or treatment response. However, whilst not linked outcome, expression as we show here. Our first to demonstrate simultaneously patients (significantly MDM2 expression), have reduced disease specific survival even though expressed rarely...

MDM2 expression, combined with increased p53 is associated reduced survival in several cancers, but particularly of interest renal cell carcinoma (RCC) where evidence suggests the presence tissue-specific p53/MDM2 pathway defects. We set out to identify MDM2-interacting proteins cells that could act as mediators/targets oncogenic effects cancers. identified non-metastatic 2, protein; NME2 (NDPK-B, NM23-B/-H2), a nucleoside diphosphate kinase, an protein using both proteomic-based strategy...

The alternatively spliced trimeric G-protein subunit XLαs, which is involved in cAMP signalling, encoded by the Gnasxl transcript of imprinted Gnas locus. XLαs deficient mice show neonatal feeding problems, leanness, inertia and a high mortality rate. Mutants that survive to weaning age develop into healthy fertile adults, remain lean despite elevated food intake. adult metabolic phenotype can be attributed increased energy expenditure, appears caused sympathetic nervous system activity. To...

MDM2 is induced by p53 in response to cellular insults such as DNA damage and can have effects upon the cell cycle that are independent or downstream of p53. We used a yeast two-hybrid screen identify proteins bind which therefore might be involved these effects. found C-terminus catalytic subunit polymerase ε (DNA pol ε), region known essential yeast. In an vitro system we confirmed could homologous regions both mouse human full-length ε. co-immunoprecipitated with from transfected H1299...

The p53 gene is the most frequently mutated in cancer and accordingly has been subject of intensive investigation for almost 30 years. Loss function due to mutations unequivocally demonstrated promote both humans model systems. As a consequence, there exists an enormous body information regarding normal biology pathobiological consequences mutation. It long recognised that analysis considerable potential as tool use diagnostic and, greater extent, prognostic settings some significant...

Abstract BACKGROUND: Recent genetic studies have implicated p53 mutation as a significant risk factor for therapeutic failure in squamous cell carcinoma of the head and neck (SCCHN). However, recent meta‐analysis literature from major anatomical subsites (larynx, oral cavity, oropharynx/hypopharynx), associations between patient survival status were ambiguous. METHODS: The authors examined cohort SCCHNs using previously developed biomarker combination that likely predicts based on p53/MDM2...

The adipokine plasminogen activator inhibitor (PAI)-1 is increased in plasma of obese individuals and exhibits expression the stomachs infected with Helicobacter. To investigate relevance gastric PAI-1, we used 1.1 kb H+/K+β subunit promoter to overexpress PAI-1 specifically mouse parietal cells (PAI-1-H/Kβ mice). We studied physiological, biochemical, behavioral characteristics these mice null for or a putative receptor, urokinase receptor (uPAR). PAI-1-H/Kβ had concentrations body mass,...

Recent studies connect MDM2 with increased cell motility, invasion and/or metastasis proposing an MDM2‐mediated ubiquitylation‐dependent mechanism. Interestingly, in renal carcinoma (RCC) p53/MDM2 co‐expression is associated reduced survival which independently linked metastasis. We therefore investigated whether expression of p53 promotes aggressive phenotypes. Our data demonstrate that motility and invasiveness RCC cells (N.B. similar results are obtained non‐RCC cells). This study shows...

Patients with mutated TP53 have been identified as having comparatively poor outcomes compared to those retaining wild-type p53 in many cancers, including squamous cell carcinomas of the head and neck (SCCHN). We examined role regulation metabolism SCCHN cells find that loss function determines Warburg effect these cells. Moreover, this metabolic adaptation creates an Achilles' heel for tumour can be exploited potential therapeutic benefit. Specifically, lacking normal function, whether...

Abstract Protein kinase Cβ (PKCβ) expressed in mammalian cells as two splice variants, PKCβI and PKCβII, functions the B cell receptor (BCR) signaling pathway contributes to development. We investigated relative role of PKCβII by generating transgenic mice where expression transgene is directed these using Eµ promoter (Eµ-PKCβIItg). Our findings demonstrate that homozygous Eµ-PKCβIItg displayed a shift from IgD + IgM dim toward populations spleen, peritoneum peripheral blood. Closer...

A major objective in the management of human papillomavirus (HPV)-positive squamous cell carcinoma head and neck (SCCHN) is to reduce long-term functional ramifications while maintaining oncological outcomes. This study examined metabolic profile HPV-positive SCCHN potential role anti-metabolic therapeutics achieve radiosensitisation as a means de-escalate radiation therapy.Three established lines were studied (UM-SCC-104, UPCI:SCC154, VU-SCC-147), together with typical TP53 mutant...