Locus Signals Case Study

Cancer is a disease caused by an uncontrolled division of abnormal cells. The DNA sequence in cells can be changed as a result of copying errors during replication. If these changes whatever their cause are left uncorrected, both growing and non-growing somatic cells might gain many mutations that they could no longer function. The relevance of DNA damage and repair to the generation of cancer was obvious when it was recognized that everything that causes cancer also cause a change in the DNA sequence. Tumor suppressor genes are protective genes and normally they limit cell growth by monitoring the speed of cell division, repair mismatched DNA and control when a cell dies. When a tumor suppressor gene is mutated cells grow

They have identified key molecules that regulate the cell cycle in all eukaryotic organisms, including yeasts, plants, animals and human. These fundamental discoveries have a great impact on all aspects of cell growth. Defects in cell cycle control may lead to the type of chromosome alterations seen in cancer cells. This may in the long-term open

To elaborate, exposure of cells to Istodax results in reduced cyclin D1 and c-Myc, followed by an increase in p53-independent p21 WAF1/Cip1 induction (VanderMolen, McCulloch, Pearce & Oberlies, 2011). The p21 induction leads to inhibition of cyclin-dependent kinase via the downregulation of cyclins, causing retinoblastoma (Rb) dephosphorylation and indirectly effecting E2F transcription activity, which results in early G1 phase cell cycle arrest (VanderMolen, McCulloch, Pearce & Oberlies,

Advance downstream, changes in the tumor silencers TSC1 and TSC2 hyper initiate motioning by mTORC1 (Laplante and Sabatini 2012). This is a critical focus of P13K-Aktsignaling. Additionally, the Ras-ERK pathway is enacted by transformations in Ras, or its downstream target Raf, that reason constitutive initiation of these proteins or by inactivation of GTPase-actuating proteins (Holes, for example, NF1, that empower the hydrolysis of GTP bound to Ras, which prompt its inactivation (Cichowski,2001).

Haller et al. (2010), have just defined the connection between p16 overexpression in the cytoplasm and p16 downregulation in the nucleus, with bad prognosis in gastrointestinal stromal tumor (24). Intriguingly, p16 downregulation in the nucleus was connected with E2F overexpression. On the other hand, p16 overexpression in the cytoplasm did not show any link with expression of E2F. These outcomes help support the proposition that p16 has various jobs in distinctive subcellular locations. It also supports the idea that nuclear p16 helps regulate control of the cell cycle. Remarkably, other regulators of the cell cycle typically found in the nucleus have been seen to be translocated to the cytoplasm in various tumors, like PTEN or p27. Both of these proteins have the capability to carry out distinctive activities from other subcellular locations (58).

| * is a common target of deletion or mutational inactivation in human tumors * an inhibitor of Cdk4-cyclin D complexes; * The loss of p16 leads to increased Cdk4-cyclin D activity

Figure 10: Simplified evolution model of the genetic landscape in melanoma development and progression30. In sequence, melanoma formation is initiated by activating mutation in BRAF from the ERK MAPK pathway, which induces senescence forming a nevus. Mutation of TERT promoter, which increases transcriptional activity, as well as disruption of cell cycle control that abrogates cell cycle arrest (elevated levels observed in melanoma in situ) are events that allows the bypass of OIS mechanism proceeding towards melanoma transformation. Copy number alteration (CNA) is observed exclusively in invasive malignant melanoma alongside mutations in p53 and PTEN tumor suppressors suggesting that these alterations are important in the event of cancer cell invasion and dissemination. Mutation burden, specifically point mutations (indicative of UVR damage) increases throughout progression. Frequency of the driver oncogenes remains constant throughout tumor progression.

Transformation-Related Protein 53, also known as TP53, is a tumor suppressor gene. It is named after its molecular mass. The gene was discovered by Arnold Levine, David Lane, and William Old in 1979 and was voted molecule of the year by science magazine in 1993. Although, it was not until 1989 that it was revealed to be a tumor suppressor gene. It was previously thought of as an oncogene. TP53 encodes for a protein, called p53 protein, that helps to regulate the cell cycle and inhibits mutations in the genome as well. Both of these functions help to conserve stability. One of the reasons for TP53’s high importance, and the extensive research on the gene, is its function to suppress cancer cells in multicellular organisms, including humans (Vijayaraj).

Proliferating cells must progress through 4 phases of cell cycle to divide (G1, S, G2 and M); however, they may exit cell cycle and enter quiescence (G0) when stressed or deprived of their biological stimuli (for example in breast cancer with estrogen deprivation)7, 8. Cyclin-dependent kinases (CDKs) play a key role in controlling cell cycle progression. Among these kinases, CDK4/6 is the key regulator of G1 to S transition by controlling transcription of genes necessary for cell cycle progression. This kinase is activated upon binding to cyclin D, leading to expression of genes required for S-phase entry9. This tightly regulated cyclin D-CDK4/6 complex is

This technique was shown to provide “more effective control of locoregional recurrence in diseases like NSCLC as well as systemic control of micrometastases,” the spread of cancer cells where secondary tumors are too small to be detected (Roth, Swisher, & Meyn, 1999; “Micrometastases”, n.d.). As explained previously in this paper, p53 is involved in many pathways influencing the cell cycle and apoptosis, making it a good candidate for targeting using gene therapy. Moreover, although cancer cells have mutations in many genes that regulate growth and repair, because p53 plays such a significant role in apoptosis, the restoration of its function will induce apoptosis in the cancer

Reversion-inducing-cysteine-rich protein with kazal motifs, also known as RECK, is a human gene, thought to be a metastasis suppressor against activated ras oncogenes [3]. It is a promising goal for controlling tumor invasion and angiogenesis. Although RECK mRNA is expressed in most of normal human tissues and untransformed cells, the protein level is low or

In a normal cell, the rate at which the normal cell grows and proliferate is tightly regulated, however, resistance to such regulation as a result of gene mutation is a hallmark of cancer. Proto-oncogenes, tumor suppressor genes, and microRNA genes are the three major groups of normal cellular genes associated with cancer(Faguet, 2015).

MacroH2A1 incorporation occurs as a late step and only after SAHF appearance by 126 DAPI staining (31). MacroH2A1 isoforms are thus highly expressed in cells 127 undergoing senescence, which is an antitumor mechanism, suggesting macroH2A1, 128 and in particular macroH2A1.1, may be a useful biomarker for senescent cells in 129 tumors such as lung and colon cancer (25, 32). MacroH2A1 seems to be 130 mechanistically dispensable for RS and DIS, as the number of -galactosidase 131 positive cells in the liver of aged macroH2A1 knock-out (KO) mice is identical to the 132 ones of aged matched wild type littermates, as well as in H2O2-treated hepatoma 133 cells KO for macroH2A1 compared to control cells (13). As said,

Inhibits the synthesis of new DNA strands so that no cell replication is possible which normally occurs at ‘S’ phase.

In the article, “TRAF6 Restricts p53 Mitochondrial Translocation, Apoptosis, and Tumor Suppression,” the experimental study looks specifically at the TRAF6 E3 ligase and its different effects on the mitochondrial tumor protein 53 (p53). The p53 gene plays a role in regulation of the cell cycle and cell fate determination. A mutation in the p53 gene is repeatedly seen in characterized human cancer cells. TRAF6 is shown to inhibit p53 activity by K63-linked ubiquitination at K24 of p53 in the cytosol. This ubiquitination inhibits the interaction between p53 and MCL-1/BAK; therefore, this restricts p53 from the mitochondria and prevents apoptosis. Furthermore, this study shows that genotoxic stress affects MCL-1/BAK and p53