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Addiction of lung cancer cells to GOF p53 is promoted by up-regulation of epidermal growth factor receptor through multiple contacts with p53 transactivation domain and promoter. - Oncotarget
Human lung cancers harboring gain-of-function (GOF) p53 alleles express higher levels of the epidermal growth factor receptor (EGFR). We demonstrate that a number of GOF p53 alleles directly upregulate EGFR. Knock-down of p53 in lung cancer cells lowers EGFR expression and reduces tumorigenicity and other GOF p53 properties. However, addiction of lung cancer cells to GOF p53 can be compensated by overexpressing EGFR, suggesting that EGFR plays a critical role in addiction. Chromatin immunoprecipitation (ChIP) using lung cancer cells expressing GOF p53 alleles showed that GOF p53 localized to the EGFR promoter. The sequence where GOF p53 is found to interact by ChIP seq can act as a GOF p53 response element. The presence of GOF p53 on the EGFR promoter increased histone H3 acetylation, indicating a mechanism whereby GOF p53 enhances chromatin opening for improved access to transcription factors (TFs). ChIP and ChIP-re-ChIP with p53, Sp1 and CBP histone acetylase (HAT) antibodies revealed docking of GOF p53 on Sp1, leading to increased binding of Sp1 and CBP to the EGFR promoter. Up-regulation of EGFR can occur via GOF p53 contact at other novel sites in the EGFR promoter even when TAD-I is inactivated; these sites are used by both intact and TAD-I mutated GOF p53 and might reflect redundancy in GOF p53 mechanisms for EGFR transactivation. Thus, the oncogenic action of GOF p53 in lung cancer is highly dependent on transactivation of the EGFR promoter via a novel transcriptional mechanism involving coordinated interactions of TFs, HATs and GOF p53.
Resistance to PPO-inhibiting herbicide in Palmer amaranth from Arkansas, USA. - Pest management science
The widespread occurrence of ALS inhibitor- and glyphosate-resistant Amaranthus palmeri has led to increasing use of protoporphyrinogen oxidase (PPO)-inhibiting herbicides in cotton and soybean. Studies were conducted to confirm resistance to fomesafen (a PPO inhibitor), determine the resistance frequency, examine the resistance profile to other foliar-applied herbicides, and investigate the resistance mechanism of resistant plants in a population collected in 2011 (AR11-LAW B), and its progenies from two cycles of fomesafen selection (C1 and C2).The frequency of fomesafen-resistant plants increased from 5% in the original AR11-LAW-B to 17% in the C2 population. The amounts of fomesafen that caused 50% growth reduction were 6-, 13-, and 21-fold greater in AR11-LAW-B, C1, and C2 populations, respectively, than the sensitive ecotype. The AR11-LAW-B population was sensitive to atrazine, dicamba, glufosinate, glyphosate, and mesotrione but resistant to ALS-inhibiting herbicides pyrithiobac and trifloxysulfuron. Fomesafen survivors from C1 and C2 populations tested positive for the PPO glycine 210 deletion previously reported in waterhemp (Amaranthus tuberculatus).These studies confirmed that Palmer amaranth in Arkansas has evolved resistance to foliar-applied PPO-inhibiting herbicide.This article is protected by copyright. All rights reserved.
Exploration on natural product anibamine side chain modification toward development of novel CCR5 antagonists and potential anti-prostate cancer agents. - Bioorganic & medicinal chemistry letters
Prostate cancer is one of the leading causes of death among males in the world. Prostate cancer cells have been shown to express upregulated chemokine receptor CCR5, a G protein-coupled receptor (GPCR) that relates to the inflammation process. Anibamine, a natural product containing a pyridine ring and two aliphatic side chains, was shown to carry a binding affinity of 1 Î¼M at CCR5 as an antagonist with potential anti-cancer activity. However, it is not drug-like according to the Lipinski's rule of five mainly due to its two long aliphatic side chains. In our effort to improve its drug-like property, a series of anibamine derivatives were designed and synthesized by placement of aromatic side chains through an amide linkage to the pyridine ring. The newly synthesized compounds were tested for their CCR5 affinity and antagonism, and potential anti-proliferation activity against prostate cancer cell lines. Basal cytotoxicity was finally studied for compounds showing potent anti-proliferation activity. It was found that compounds with hydrophobic substitutions on the aromatic systems seemed to carry more promising CCR5 binding and prostate cancer cell proliferation inhibition activities.Published by Elsevier Ltd.
MDM2 overexpression, activation of signaling networks, and cell proliferation. - Sub-cellular biochemistry
Frequent overexpression of MDM2 in human cancers suggests that the protein confers a survival advantage to cancer cells. However, overexpression of MDM2 in normal cells seems to restrict cell proliferation. This review discusses the cell growth regulatory functions of MDM2 in normal and genetically defective cells to assess how cancer cells evade the growth-restricting consequence of MDM2 overexpression. Similar to oncoproteins that induce a DNA damage response and oncogene induced senescence in non-transformed cells, MDM2 induces G1-arrest and intra-S phase checkpoint responses that control untimely DNA replication in the face of genetic challenges.
Impact of targeted specific antibiotic delivery for gut microbiota modulation on high-fructose-fed rats. - Applied biochemistry and biotechnology
The objective of present investigation was to study the effect of gut microbiota alteration by oral administration of targeted delivery of pH sensitive cefdinir microspheres to high-fructose-fed (HFD) rats. Rats were fed with a high-fructose diet with or without cefdinir microsphere administration for 30 days. The fecal microbiota community, oral glucose tolerance, the markers of liver injury, plasma and hepatic lipids profile, and histological evaluation were investigated. The levels of blood glucose, liver injury markers, lipid profile in plasma and liver, and fat tissue were significantly increased in high-fructose-fed rats. However, after pH-sensitive cefdinir microsphere administration, the elevation of these parameters was significantly suppressed. Cef EL significantly lowered the increased AST (pâ€‰<â€‰0.05) and ALT (pâ€‰<â€‰0.001) levels in HFD group. There is a significant lower (pâ€‰<â€‰0.01) AUCglucose level in Cef EL group than HFD group The histological changes in the liver and the small and large intestines were more profound in HFD group as compared to cefdinir-treated HFD and control groups. Feeding of cefdinir microsphere sustained lactobacilli and bifidobacteria and significantly decreased (pâ€‰<â€‰0.05) the number of Enterobacteriaceae induced by HFD. Experimental evidences demonstrated that the effectiveness of pH-specific cefdinir microsphere on reducing insulin resistance and development of metabolic changes in high-fructose-fed rats and suggested that it may be a promising therapeutic agent in treating type 2 diabetes. Intestinal-targeted antibiotic delivery needs to be further explored for its therapeutic applications.
Appearance can be deceptive: Dentigerous cyst crossing the midline. - National journal of maxillofacial surgery
Dentigerous cyst is a developmental odontogenic cyst, which develops by accumulation of fluid between reduced enamel epithelium and the tooth crown of an unerupted tooth. Dentigerous cysts are usually solitary, slow growing, asymptomatic lesions that are incidentally found during routine radiographs They most frequently involve the mandibular third molar followed in order of frequency by the maxillary canine, mandibular second pre-molar and maxillary third molar. Occasionally, these cysts become painful when infected causing swelling and erythema. The cyst is usually small, however, when large, results in the expansion and thinning of the cortex leading to pathological fracture. Radiographic features are specific to the lesion characterized by a well-defined radiolucency circumscribed by a sclerotic border, associated with the crown of an impacted or unerupted tooth. Dentigerous cysts are treated most commonly by enucleation, Marsupialization and decompression of cyst by fenestration. The criteria for selecting the treatment modality is based on the age, size, location, stage of root development, position of the involved tooth and relation of the lesion to the adjacent tooth and vital structure. The prognosis is an excellent when the cyst is enucleated and recurrence is rare. In this article, we present a case of a Dentigerous cyst in an 80-year-old man in the anterior aspect of the mandible enveloping an impacted canine and crossing the midline but with no clinical expansion or discomfort.
The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing. - Nucleic acids research
Conventional paradigm ascribes the cell proliferative function of the human oncoprotein mouse double minute2 (MDM2) primarily to its ability to degrade p53. Here we report that in the absence of p53, MDM2 induces replication stress eliciting an early S-phase checkpoint response to inhibit further firing of DNA replication origins. Partially synchronized lung cells cultured from p53-/-:MDM2 transgenic mice enter S phase and induce S-phase checkpoint response earlier than lung cells from p53-/- mice and inhibit firing of DNA replication origins. MDM2 activates chk1 phosphorylation, elevates mixed lineage lymphoma histone methyl transferase levels and promotes checkpoint-dependent tri-methylation of histone H3 at lysine 4, known to prevent firing of late replication origins at the early S phase. In the absence of p53, a condition that disables inhibition of cyclin A expression by MDM2, MDM2 increases expression of cyclin D2 and A and hastens S-phase entry of cells. Consistently, inhibition of cyclin-dependent kinases, known to activate DNA replication origins during firing, inhibits MDM2-mediated induction of chk1 phosphorylation indicating the requirement of this activity in MDM2-mediated chk1 phosphorylation. Our data reveal a novel pathway, defended by the intra-S-phase checkpoint, by which MDM2 induces unscheduled origin firing and accelerates S-phase entry of cells in the absence of p53.
Gain-of-Function Activity of Mutant p53 in Lung Cancer through Up-Regulation of Receptor Protein Tyrosine Kinase Axl. - Genes & cancer
p53 mutations are present in up to 70% of lung cancer. Cancer cells with p53 mutations, in general, grow more aggressively than those with wild-type p53 or no p53. Expression of tumor-derived mutant p53 in cells leads to up-regulated expression of genes that may affect cell growth and oncogenesis. In our study of this aggressive phenotype, we have investigated the receptor protein tyrosine kinase Axl, which is up-regulated by p53 mutants at both RNA and protein levels in H1299 lung cancer cells expressing mutants p53-R175H, -R273H, and -D281G. Knockdown of endogenous mutant p53 levels in human lung cancer cells H1048 (p53-R273C) and H1437 (p53-R267P) led to a reduction in the level of Axl as well. This effect on Axl expression is refractory to the mutations at positions 22 and 23 of p53, suggesting that p53's transactivation domain may not play a critical role in the up-regulation of Axl gene expression. Chromatin immunoprecipitation (ChIP) assays carried out with acetylated histone antibodies demonstrated induced histone acetylation on the Axl promoter region by mutant p53. Direct mutant p53 nucleation on the Axl promoter was demonstrated by ChIP assays using antibodies against p53. The Axl promoter has a p53/p63 binding site, which however is not required for mutant p53-mediated transactivation. Knockdown of Axl by Axl-specific RNAi caused a reduction of gain-of-function (GOF) activities, reducing the cell growth rate and motility rate in lung cancer cells expressing mutant p53. This indicates that for lung cancer cell lines with mutant p53, GOF activities are mediated in part through Axl.
Allele specific gain-of-function activity of p53 mutants in lung cancer cells. - Biochemical and biophysical research communications
p53 mutations are mostly single amino acid changes resulting in expression of a stable mutant protein with "gain of function" (GOF) activity having a dominant oncogenic role rather than simple loss of function of wild-type p53. Knock-down of mutant p53 in human lung cancer cell lines with different endogenous p53 mutants results in loss of GOF activity as shown by lowering of cell growth rate. Two lung cancer cell lines, ABC1 and H1437, carrying endogenous mutants p53-P278S and -R267P, show reduction in growth rate on knock-down on p53 levels. However, whereas reduction of the p53 level induces loss of tumorigenicity in nude mice for ABC1 cells, it escalates tumorigenicity for H1437 cells. We have tested their transactivation potential on p53 target gene promoters by performing transient transcriptional assays in the p53-null H1299 lung cancer cell line. Interestingly, while the mutant p53 target promoter Axl was activated by both the mutants, the p21 promoter was activated by p53-R267P and wild-type p53 but not by p53-P278S; showing a clear difference in transcriptional activity between the two mutants. Our results demonstrate allele specificity between GOF p53 mutants and attempt to show that the specificity is dependent on the transactivation property of GOF p53; it also suggests importance of p21 activation in tumor suppression by p53.Copyright Â© 2012 Elsevier Inc. All rights reserved.
Human Oncoprotein MDM2 Up-regulates Expression of NF-ÎºB2 Precursor p100 Conferring a Survival Advantage to Lung Cells. - Genes & cancer
The current model predicts that MDM2 is primarily overexpressed in cancers with wild-type (WT) p53 and contributes to oncogenesis by degrading p53. Following a correlated expression of MDM2 and NF-ÎºB2 transcripts in human lung tumors, we have identified a novel transactivation function of MDM2. Here, we report that in human lung tumors, overexpression of MDM2 was found in approximately 30% of cases irrespective of their p53 status, and expression of MDM2 and NF-ÎºB2 transcripts showed a highly significant statistical correlation in tumors with WT p53. We investigated the significance of this correlated expression in terms of mechanism and biological function. Increase in MDM2 expression from its own promoter in transgenic mice remarkably enhanced expression of NF-ÎºB2 compared with its non-transgenic littermates. Knockdown or elimination of endogenous MDM2 expression in cultured non-transformed or lung tumor cells drastically reduced expression of NF-ÎºB2 transcripts, suggesting a normal physiological role of MDM2 in regulating NF-ÎºB2 transcription. MDM2 could up-regulate expression of NF-ÎºB2 transcripts when its p53-interaction domain was blocked with Nutlin-3, indicating that the MDM2-p53 interaction is dispensable for up-regulation of NF-ÎºB2 expression. Consistently, analysis of functional domains of MDM2 indicated that although the p53-interaction domain of MDM2 contributes to the up-regulation of the NFÎºB2 promoter, MDM2 does not require direct interactions with p53 for this function. Accordingly, MDM2 overexpression in non-transformed or lung cancer cells devoid of p53 also generated a significant increase in the expression of NF-ÎºB2 transcript and its targets CXCL-1 and CXCL-10, whereas elimination of MDM2 expression had the opposite effects. MDM2-mediated increase in p100/NF-ÎºB2 expression reduced cell death mediated by paclitaxel. Furthermore, knockdown of NF-ÎºB2 expression retarded cell proliferation. Based on these data, we propose that MDM2-mediated NF-ÎºB2 up-regulation is a combined effect of p53-dependent and independent mechanisms and that it confers a survival advantage to lung cancer cells.
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300 Ferry Road Apt 506 Galveston, TX 77550
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