Presented by Kevin Galacgac
One of the factors that contribute to cancer is immortalization of cells. In normal human cells, the ends of chromosomes called telomeres are shortened with each round of cell division. When the telomeres become too short, cells either go through irreversible cell cycle arrest (senescence) or programmed cell death (apoptosis). In contrast, cancer cells maintain their telomere lengths by activating telomerase, which helps to stabilize telomeres by adding DNA repeats. Human telomerase reverse transcriptase (hERT) is the component of telomerase that determines its activity.
In this study, researchers examined possible relationships between survivin and telomorase activity in human colon cancer cells. Survivin is a member of the inhibitor of apoptosis protein (IAP) family. It blocks apoptosis by inhibiting activation of apoptosis effectors. Experimental data showed that survivin up-regulates telomerase activity by enhancing the DNA binding activities of specificity protein (Sp1) and c-Myc to the hTERT promoter by increasing their phosphorylation. In addition to inhibiting apoptosis, the researchers showed that survivin causes cancer by immortalizing normal cells.
telomere and telomerase information
What is the relationship between the tumor suppressor gene p53 and the nuclear signaling protein beta-catenin during bone differentiation? It has been shown that during tumorigenesis and DNA damage there is some sort of ³cross talk² between the p53 gene and the beta-catenin pathways. The p53 tumor suppressor gene acts by sensing damaged DNA and causing the cell to undergo apoptosis. This study has shown that the p53 gene may not be limited to tumor suppression but also plays an important role in tissue organization during development. In order to determine the relationship between the two proteins estrogen treatment of osteoblasts were used during osteoblast differentiation.
Rat osteosarcoma cell line ROS 17/2.8, were exposed to 17-beta estradiol (E2) to study the expression of beta-catenin. Both p53 functional activity as well as alkaline phosphatase activity increased in a similar fashion as beta-catenin. Determination of the direct relationship between alkaline phosphatase and beta-catenin was analyzed using treatment of LiCl. LiCl is said to activate beta-catenin thereby causing an increase in alkaline phosphatase. Experimental data showed that beta-catenin activity adjusts to a certain proportion when estrogen induced osteoblast differentiation occurs. The increase of beta-catenin is also directly related to an increase in p53 and alkaline phosphatase.
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Presented by Gilian Mager
The degree of metastatic tumor growth usually determines whether a cancer becomes fatal or not. Normally, p27kip1 is a tumor suppressor or CDK inhibitor classified under the CIP/KIP family. It acts similarly to p21 in that it inhibits the formation and, therefore, activity of cyclin-CDK complexes. This, in turn, helps to regulate the cell cycle by preventing entry into the S phase.
However, p27 has also been shown to be involved in cell motility. Researchers have demonstrated that p27 is exported out of nucleus and into the cytoplasm where it interacts either directly or indirectly to induce cytoskeleton rearrangement in the cell. This has been shown to occur through the signaling of Hepatocyte growth factor (HGF) to its receptor c-Met. C-Met then activates HGF-activated kinase which phosphorylates p27 to move it out of the nucleus. Numerous experiments were done to show the presence of p27 in the cytoplasm when HGF signaling was induced and its cell motility abilities through a comparison of fibroblast migration in p27 WT and defected p27 -/-.
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More about p27 function and CDK inhibitors
p27 expression in cancer cells
p27 as a tumor suppressor gene and its misregulation in cancer
p27 mutations in breast cancer
What is p53, and what does it do? The protein p53 is involved in reducing the risk of cancer through production of apoptosis. The protein p53 acts in response to DNA Damage, or the creation of oncogenes. The frequency of p53 is very low in human tumors leading us to believe that p53 inactivation leads to over expression of viral proteins. By rebuilding the amount of p53 with its proper function into specific targets, it can possibly be used for cancer treatment. Renal Cell Carcinomas (RCC) is a very common cancer in which curable options is slim. In addition, RCC shows a repression of the p53 protein. This repression of p53 is dominant, which also makes it possible to prescribe drugs. Due to this availability, a target can be approached to restore the function of p53. The researchers choose a 9-aminoacridine (9AA) as well as Quinacrine (QC) an antimalaria drug to serve in activating p53 in tumor cells, which leads to inhibition of active NF- B in tumor cells. NF- B is a benefit for tumor cells because it inhibits apoptosis. The researchers of this paper illustrate by the tumor cell suppressing the p53 protein and having active NF- B signaling simultaneously, it is possible to conduct the reverse of this process and simultaneously inhibiting NF- B and promote activation of p53 by just a single molecule.
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p53 protein-DNA complex and brief explanation of Cancer
Presented by Juliana Gazallo
Cell cycle arrest is caused by tumor suppressor p53. p53 also causes cell cycle apoptosis. The perp gene, which encodes a transmembrane protein of the Pmp22 family, is expressed in cells that undergo p53-dependent apoptosis. Perp is a target of p53; overexpression of perp induces apoptosis.
Perp's role in normal development is unclear. In this study, a zebrafish perp homolog is isolated and characterized. Perp's expression in normal development is p53-independent in specific cell types and tissues. Therefore, aside from perp's proapoptotic function in stressed cells, perp regulates tissue-specific cell survival in normal zebrafish development.
PubMed Related article: Perp is a mediator of p53-dependent apoptosis in diverse cell types.
Analysis of Perp, an apoptosis and adhesion-associated p53/p63 target gene
Presented by Nahal Kaivan
Researchers take a closer look at apoptosis and its effects on the Sindbis Virus in weanling mice. Bcl-2 and BAX are the two proteins that are used in observation and experimentation. Bcl-2 acts as expected in experimentation, but BAX usually a pro-apoptotic protein reverses its role and assists in preventing cell-death in the mice in relation to the virus. Though apoptosis is regulated in relation to contraction of the virus, it is not prominent enough/regulative in preventing paralysis.
Experimentation began by constructing a much more virulent vector of the virus from some of its strains. The vector made also caused spinal chord infection and hind-limb paralysis in addition to the other effects of the virus.
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Full text of article
1. Nature: Bax-independent inhibition of apoptosis by Bcl-XL
2. Nature Medicine: Inhibition of virus-induced neuronal apoptosis by Bax
3. Annual Review of Neuroscience: Apoptosis in Neural Development and Disease
5. Microbiology: Bcl-2 protects mice against fatal alphavirus encephalitis
Presented by Joel Martin
Apoptosis is a term that is also known as "programmed cell death." It is the process whereby a cell essentially "commits suicide." It consists of several basic properties which include nuclear condensation, chromosome fragmentation, cell membrane "blebbing", phagocytosis by nearby cells, and an active "suicide" program which usually requires gene activation (transcription and translation). The experiment conducted by Celese Tríbulo and his colleagues looks at two transcription factors, Slug and msx1, and the effect they have on the apoptosis of neural crest cells. Apoptosis is common in the developing nervous system to create definition, and they wanted to determine how Slug and msx1 help define the neural crest. The results of their experiment showed that these two transcription factors do indeed play a key role in doing this. They found that Slug acts to inhibit apoptosis while msx1 encourages apoptosis. This interaction of opposing forces is what helps create the precise regions of the neural crest. Tríbulo and his colleagues also found an interaction between these two transcription factors and the proteins Bcl2 and Bax. For example, when Bax and Slug mRNA were both injected into animal caps and in whole embryos, through TUNEL staining they found that Slug was no longer preventing apoptosis.
Links:
Science Direct Full Text of the Article
Xenbase: A Xenopus Web Resource
Apoptosis, Caspase, and Cell Death Resources
Presented by Emily Correll
The fusion of the avian upper lip has been found to be linked to the signaling of the bone morphogenetic proteins (BMPs) and Noggin. BMPs are part of the TGF-ß super family of proteins. Interrupting the signaling pathways of BMPs and Noggin causes the formation of a cleft lip and palate. The signaling pathways from the BMP's and noggin genes either promote cell survival or the thinning of the cells through programmed cell death which leads to the fusion of the lip.
Researchers tested the function and of BMPs and Noggin by implanting beads within the face of the developing embryo to examine to results and to determine the role of the specific BMP molecules (BMP2, BMP4, BMP7 and Noggin) in the fusion of the upper lip.
Distinct functions for Bmp signaling in lip and palate fusion in mice
Fate map of the developing chick face
Presented by Dennis Teubner
This paper examined the effects of Wnts on the induction of neural crest cells, and if the Wnt's posteriorizing of anterior neural tissue can be dissociated from this induction. Also, this paper investigates whether downstream Wnt signaling components are requirements for neural crest induction and specification. Neural crest cells are pluripotent progenitor cells created at the boundary of neural ectoderm and non-neural ectoderm. These neural crest cells delaminate from the dorsal neural tube and migrate throughout the embryo. These cells then differentiate into many cell types including peripheral neurons, craniofacial bone and cartilage, pigment cells, and more. It has been proposed that fibroblast growth factor, retinoic acid, and Wnt signaling are possible inducers of neural crest. Wnt signaling has been shown to be a requirement in neural crest induction by experiments with Wnt antagonists, such as GSK-3B, which reduce neural crest expression. Wnt signaling also induces posterior neural development and suppresses anterior development. It is because of this that it was proposed that neural crest induction is a by product of this posteriorization. It has also been proposed that downstream elements in the canonical Wnt pathway play an important role in neural crest induction and later neural crest specification. Experiments preformed included inhibiting posterizing ability, and expanding gene expression (Slug) using B-catenin. This study found the induction of neural crest by Wnts, and the posteriorizing of anterior neural tissue by Wnts to be distinct and separable processes. Furthermore, this study found that canonical Wnt signaling is a requirement for neural crest induction.
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PubMed Abstract of the Article
Presented by Heather Beeson
The neural cell recognition molecule, L1, has been linked to biological complexity involving human disease mutations. L1 is a member of a subfamily of cell adhesion molecules, whose expression resides primarily in the nervous system, functioning in axonal path finding and cell migration.
Researchers have found that mutations in the L1 gene are responsible for an X-linked recessive neurological disorder, hydrocephalus, as well as other severe symptoms involved in what has been termed the CRASH syndrome. Analysis of the human pathological mutations in L1 is complemented in the nervous system of mice. Some aspects of the phenotype in mice vary markedly between different genetic lineages. The development and phenotypic variability of dilated ventricles of mutant mice encompassing this L1-related hydrocephalus, has suggested that additional genes may play a modifying role in influencing the severity of this L1 deficiency.
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PubMed Abstract of the Article
Disruption of the Mouse L1 Gene
Errors in Corticospinal Axon Guidance in Mice