The p53 tumor suppressor is a key mediator of cellular responses to various stresses. Here, we show that under conditions of basal physiologic and cell-culture stress, p53 inhibits expression of the ...CD44 cell-surface molecule via binding to a noncanonical p53-binding sequence in the CD44 promoter. This interaction enables an untransformed cell to respond to stress-induced, p53-dependent cytostatic and apoptotic signals that would otherwise be blocked by the actions of CD44. In the absence of p53 function, the resulting derepressed CD44 expression is essential for the growth and tumor-initiating ability of highly tumorigenic mammary epithelial cells. In both tumorigenic and nontumorigenic cells, CD44's expression is positively regulated by p63, a paralogue of p53. Our data indicate that CD44 is a key tumor-promoting agent in transformed tumor cells lacking p53 function. They also suggest that the derepression of CD44 resulting from inactivation of p53 can potentially aid the survival of immortalized, premalignant cells.
Epithelial ovarian tumors present a complex clinical, diagnostic and therapeutic challenge because of the difficulty of early detection, lack of known precursor lesions and high mortality rates. ...Endometrioid ovarian carcinomas are frequently associated with endometriosis, but the mechanism for this association remains unknown. Here we present the first genetic models of peritoneal endometriosis and endometrioid ovarian adenocarcinoma in mice, both based on the activation of an oncogenic K-ras allele. In addition, we find that expression of oncogenic K-ras or conditional Pten deletion within the ovarian surface epithelium gives rise to preneoplastic ovarian lesions with an endometrioid glandular morphology. Furthermore, the combination of the two mutations in the ovary leads to the induction of invasive and widely metastatic endometrioid ovarian adenocarcinomas with complete penetrance and a disease latency of only 7 weeks. The ovarian cancer model described in this study recapitulates the specific tumor histomorphology and metastatic potential of the human disease.
Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) ...represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.
Missense mutations in the gene TP53, which encodes p53, one of the most important tumor suppressors, are common in human cancers. Accumulated mutant p53 proteins are known to actively contribute to ...tumor development and metastasis. Thus, promoting the removal of mutant p53 proteins in cancer cells may have therapeutic significance. Here we investigated the mechanisms that govern the turnover of mutant p53 in nonproliferating tumor cells using a combination of pharmacological and genetic approaches. We show that suppression of macroautophagy by multiple means promotes the degradation of mutant p53 through chaperone-mediated autophagy in a lysosome-dependent fashion. In addition, depletion of mutant p53 expression due to macroautophagy inhibition sensitizes the death of dormant cancer cells under nonproliferating conditions. Taken together, our results delineate a novel strategy for killing tumor cells that depend on mutant p53 expression by the activation of chaperone-mediated autophagy and potential pharmacological means to reduce the levels of accumulated mutant p53 without the restriction of mutant p53 conformation in quiescent tumor cells.
Tumor angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate that the critical step in establishing the angiogenic capability of human ...cells is the repression of the critical anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. We have uncovered the signaling pathway leading from Ras to Tsp-1 repression. Ras induces the sequential activation of PI3 kinase, Rho, and ROCK, leading to activation of Myc through phosphorylation; phosphorylation of Myc via this mechanism enables it to repress Tsp-1 expression. We thus describe a novel mechanism by which the cooperative activity of the oncogenes, ras and myc, leads directly to angiogenesis and tumor formation.
Prolongation of ovarian epithelial cancer survival depends on early detection or improved responses to chemotherapy. Gains in either have been modest at best. Understanding the diverse pathogenesis ...of this disease is critical to early intervention or prevention. This review addresses six important variables, including (i) cell of origin, (ii) site of origin, (iii) initial genotoxic events, (iv) risks imposed by hereditary and other promoting conditions, (v) subsequent factors that promote different patterns of metastatic spread, and (vi) prospects for intervention. This review proposes two distinct pathways to pelvic epithelial cancer. The first initiates in ovarian surface epithelium (OSE), Mullerian inclusions or endometriosis in the ovary. The second arises from the endosalpinx and encompasses a subset of serous carcinomas. The serous carcinogenic sequence in the distal fallopian tube is described and contrasted with lower grade serous tumors based on tumour location, earliest genetic change and ability (or lack of) to undergo terminal (ciliated) differentiation. Ultimately, a clear understanding of tumour origin and the mechanism(s) leading to the earliest phases of the serous and endometrioid carcinogenic sequences may hold the greatest promise for designing prevention strategies and/or developing new therapies.
The Temperature Laboratory at TUBITAK UME initiated a study which focused on the construction of freezing point cells of ITS-90 as primary temperature standards. The first cell constructed within the ...scope of this study was an open tin freezing point cell and the results were in good agreement with the reference tin fixed point cell of UME. The second set of cells constructed was two open zinc freezing point cells. The design of these cells is similar to the tin freezing point cell. After construction, all the home-made cells were evaluated by analyzing their melting and freezing curves. Finally comparison measurements were performed between the current laboratory reference zinc cell and all newly constructed cells.
Distribution and occurrence of
Archaea and methanogenic activity in a laboratory scale, completely mixed anaerobic reactor treating pharmaceutical wastewaters were investigated and associated with ...reactor performance. The reactor was initially seeded with anaerobic digester sludge from an alcohol distillery wastewater treatment plant and was subjected to a three step feeding strategy. The feeding procedure involved gradual transition from a glucose containing feed to a solvent stripped pharmaceutical wastewater and then raw pharmaceutical wastewater. During the start-up period, over 90% COD removal efficiency at an organic loading rate (OLR) of 6
kg
COD
m
−3
d
−1 was achieved with glucose feeding, and acetoclastic methanogenic activity was 336
ml CH
4
gTVS
−1
d
−1. At the end of the primary loading, when the feed contained solvent stripped pharmaceutical wastewater at full composition, 71% soluble COD removal efficiency was obtained and acetoclastic methanogenic activity decreased to half of the rate under glucose feed (166
ml
CH
4
gTVS
−1
d
−1). At the end of secondary loading with 60% (w/v) raw pharmaceutical wastewater, COD removal dropped to zero and acetoclastic methanogenic activity fell to less than 10
ml
CH
4
gTVS
−1
d
−1. Throughout the course of the experiment, microbial community structure was monitored by DGGE analysis of 16S rRNA gene fragments. Five different archaeal taxa were identified and the predominant archaeal sequences belonged to methanogenic
Archaea. Two of these showed greatest sequence identity with
Methanobacterium formicicum and
Methanosaeta concilii. The types of
Archaea present changed little in response to changing feed composition but the relative contribution of different organisms identified in the archaeal DGGE profiles did change.
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