https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

Global strategy for asthma management and prevention

http://aiocm.org/member/Immunity,%20Inflammation,%20and%20Cancer.pdf

Immunity, Inflammation, and Cancer

p53, the Cellular Gatekeeper for Growth and Division

Apoptosis - the regulated destruction of a cell - is a complicated process. The decision to die cannot be taken lightly, and the activity of many genes influence a cell's likelihood of activating its self-destruction programme. Once the decision is taken, proper execution of the apoptotic programme requires the coordinated activation and execution of multiple subprogrammes. Here I review the basic components of the death machinery, describe how they interact to regulate apoptosis in a coordinated manner, and discuss the main pathways that are used to activate cell death.

The biochemistry of apoptosis

Breast cancer, like any other human cancer, results from the accumulation of mutations that deregulate critical cellular processes, such as cell proliferation and death. Activation of oncogenes and inactivation of tumor suppressor genes are common events during cancer initiation and progression and often determine treatment responsiveness. Thus, recapitulating these events in mouse cancer models is critical for unraveling the molecular mechanisms involved in tumorigenesis and for interrogating their possible impact on response to anticancer drugs. We have developed a novel mouse mammary epithelial cell model, which replicates the steps of epithelial tumor progression and takes advantage of the power of mouse genetics and the ability to assess three‐dimensional morphogenesis in the presence of extracellular matrix to model human breast cancer.

A mouse mammary epithelial cell model to identify molecular mechanisms regulating breast cancer progression.

PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer.

BACKGROUND

Epothilones are a promising class of drugs in clinical trials of prostate cancer that target the microtubules, similar to taxanes, and induce apoptosis in taxane resistant tumors. The tumor suppressor p53 is one important molecular mechanism of chemotherapy resistance that in some studies predicted tumor sensitivity to paclitaxel. We hypothesized that epothilone induced cytotoxicity would be influenced by the status of p53 in prostate cells.



METHODS

LNCaP, DU145, and a transformed rat prostate (RP) epithelial cell line with a temperature sensitive mutant p53 (val 135) were studied for the effect of epothilone on cell viability, cell cycle, and cell cycle checkpoint proteins.



RESULTS

Epothilone had greater cytotoxicity in p53 mutant cancer cells compared to wild type cells. We confirmed our findings by creating a transformed RP epithelial cell line with a temperature sensitive mutant p53 (val 135). Using a tetrazolium (MTT) assay we found that epothilone (100 nM) decreased cell viability in RP cells by 90% with mutant p53 compared to 45% with wild type p53 (P < 0.01). Epothilone induced G2/M arrest in 50% of cells with mutant p53 compared to 25% with wild type p53 (P < 0.01). To begin to understand mechanism of epothilone induced G2/M arrest, we assessed cell cycle checkpoint proteins. We found that the effect to enhance G2/M cell cycle arrest was associated with dephosphorylation of cdc2 in both p53 wild type and p53 mutant RP cells.



CONCLUSIONS

These results demonstrate that epothilone is more active against transformed prostate epithelial cells with mutant compared to wild type p53. Epothilone is capable of dephosphorylation of cdc2 in both p53 wild type and mutant cells, which is associated with G2/M cell cycle arrest. These data provide a basis for further study of p53, and the phosphorylation status of cdc-2, as markers for epothilone sensitivity in clinical studies. © 2004 Wiley-Liss, Inc.

Epothilone induced cytotoxicity is dependent on p53 status in prostate cells.

BCCIP is a BRCA2- and CDKN1A(p21)-interacting protein that has been implicated in the maintenance of genomic integrity. To understand the in vivo functions of BCCIP, we generated a conditional BCCIP knockdown transgenic mouse model using Cre-LoxP mediated RNA interference. The BCCIP knockdown embryos displayed impaired cellular proliferation and apoptosis at day E7.5. Consistent with these results, the in vitro proliferation of blastocysts and mouse embryonic fibroblasts (MEFs) of BCCIP knockdown mice were impaired considerably. The BCCIP deficient mouse embryos die before E11.5 day. Deletion of the p53 gene could not rescue the embryonic lethality due to BCCIP deficiency, but partially rescues the growth delay of mouse embryonic fibroblasts in vitro. To further understand the cause of development and proliferation defects in BCCIP-deficient mice, MEFs were subjected to chromosome stability analysis. The BCCIP-deficient MEFs displayed significant spontaneous chromosome structural alterations associated with replication stress, including a 3.5-fold induction of chromatid breaks. Remarkably, the BCCIP-deficient MEFs had a ∼20-fold increase in sister chromatid union (SCU), yet the induction of sister chromatid exchanges (SCE) was modestly at 1.5 fold. SCU is a unique type of chromatid aberration that may give rise to chromatin bridges between daughter nuclei in anaphase. In addition, the BCCIP-deficient MEFs have reduced repair of irradiation-induced DNA damage and reductions of Rad51 protein and nuclear foci. Our data suggest a unique function of BCCIP, not only in repair of DNA damage, but also in resolving stalled replication forks and prevention of replication stress. In addition, BCCIP deficiency causes excessive spontaneous chromatin bridges via the formation of SCU, which can subsequently impair chromosome segregations in mitosis and cell division.

Eileen White

Papers

A mouse mammary epithelial cell model to identify molecular mechanisms regulating breast cancer progression.

PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer.

Epothilone induced cytotoxicity is dependent on p53 status in prostate cells.

Essential Roles of BCCIP in Mouse Embryonic Development and Structural Stability of Chromosomes

Adenovirus-Mediated Cytotoxicity of Chronic Lymphocytic Leukemia Cells