2013).The main biochemical characteristics of apoptosis include caspase activation and DNA fragmentation (Madeo, Frohlich et al. 1997, Du, Fang et al. 2000). Apoptosis is induced by various physiological or toxic signals such as chemotherapeutics, DNA damage, ultraviolet irradiation, oxidative stress and endoplasmic reticulum stress. Impaired cell death is a characteristic of cancer cells, determining their resistance to apoptotic signals, (Adams and Cory 2007, Hartman and Czyz 2013) which is one of the six essential alterations in cell biological capabilities acquired during the multistep development of human tumours (Hanahan and Weinberg 2011, Hartman and Czyz 2013) and remains critical in effective cancer treatment strategies (Adams and Cory 2007).
MAPK Pathway The MAPK pathway is one of the well studied pathways which connect different types of membrane receptors when there is mitogenic differentiation or stimulation. This pathway is involved in cell differentiation, proliferation, apoptosis and migration. Regulation of migration is crucial in various instances such as the embryonic cell layer movement during development, wound healing, inflammation etc. While unregulated migration is the hallmark of tumor invasion. Cells will migrate towards the direction of chemical signals like epidermal growth factor, keratin growth factor, insulin like growth factor etc (van Golen et al., 2002).
Cancer causing genes can be divided into two classes: 1.) Tumor suppressor genes 2.) Oncogenes. Tumor suppressors if underexpressed are unable to check cell proliferation, resulting in tumor formation. On the other hand, the same results if proto-oncogenes (the precursors of oncogenes) are overexpressed or activated.
One of the recent developments in the research behind oncogenesis and its relationship to cancer is the theory of “oncogenic addiction”. This theory explains the phenomena of “a tumor cell seemingly exhibiting dependence on a single oncogenic pathway or protein for its sustained proliferation and/or survival” (Sharma & Settleman 2007). These findings suggest that there may be a way to “switch off the crucial pathway of dependence”, which in theory should negatively affect or inhibit the cancer, “while sparing normal cells that are not similarly addicted” (Sharma & Settleman 2007). This has been established with the ability to inactivate “counterparts of oncogenic proteins in normal tissues” and see that there is toleration without “obvious consequences” (Sharma & Settleman 2007). This is the concept of “addiction” in cancer, and the dependence on particular genes to activate prolifer... ... middle of paper ... ...need to be developed to begin this study, we can infer from past research the steps in which determination of these relationships could be done.
The oncogenes encode proteins involved in the cell cycle that also stimulate growth and division of the cell. These proteins accelerate the cell cycle by allowing cells to proceed directly from either the G0 or the G1 phase to the S phase or mitosis. One particular way includes cell surface receptors binding to growth factors. Growth factors include either proteins that interact with DNA to begin replication or signaling molecules that link receptors to the initiation of replication.1 Conversion of a Proto-Oncogene to an Oncogene In a normal cell, genes coding for proteins that control cell division and growth are called proto-oncogenes. However, a mutation can permanently activate proteins that are both active and inactive.
Proto-oncogenes are those genes that control normal but essential cell processes that keep cell growth and death in check. Two important categories are apoptosis genes, which regulate cell death, and tumor suppressor genes, which decrease cell propagation 1 . If these genes were mutated to the point where they cannot produce a functioning protein, cell division would continue far past what it was supposed to and unhealthy cells would be allowed to live and continue to multiply. This is what creates a malignant tumor. Certain conditions in the body can also promote the growth of cancer cells.
Cancer occurrs by the production of multiple mutations in a single cell that causes it to proliferate out of control. Cancer cells often different from their normal neighbors by a host of specific phenotypic changes, such as rapid division rate, invasion of new cellular territories, high metabolic rate, and altered shape. Some of those mutations may be transmitted from the parents through the germ line. Others arise de novo in the somatic cell lineage of a particular cell. Cancer-promoting mutations can be identified in a variety of ways.
Cancer (otherwise defined medically as a malignant neoplasm) is a group of diseases which are associated with dynamic aberrations in the genome and consequent losses in the regulatory mechanisms which govern normal cell proliferation and homeostasis. There are two important classes of genes involved in the control and homeostasis of the cell-cycle both of which play key roles with respect to cancer – the oncogenes and tumour-suppressor genes. Oncogenic precursors known as proto-oncogenes are genes encoding proteins involved in signalling systems that control cell growth and differentiation – typically being involved in signal transduction pathways and execution of mitogenic signalling (Elliot and Elliot, 2009). Cancer cell mutations, or over expression, in proto-oncogenes generate oncogenic variants (alleles) which lead to what can be considered dominant 'gain of function' mutations endowing them with enhanced or novel functions relative to their proto-oncogene precursors (Fearon, 1999). Tumour-suppressor genes on the other hand function as checkpoints in the cell-cycle (Elliot and Elliot, 2009).
Cells are also stimulated to divide through the two proteins, cyclins and cyclin-dependent kinases. When these two join together, this stimulates cell division. These proteins act on the growth inhibitor proteins P53 and PRP, which are growth inhibitor proteins. Tumours may be malignant, spreading or benign, non-spreading. Malignant tumours are aggressive, invasive, and mobile.
This research studies about the unique role of HAUSP in the p53-Mdm2 pathway. p53 is a tumor suppressor gene, so not only does it stop the formation of tumors but can also arrest growth and initiate apoptosis. Stabilization of p53 is important for these functions to occur. Now ubiquitination of proteins is useful in many cellular processes and Mdm2 mediates p53's degradation. Mdm2 is an oncoprotein that binds and blocks the N terminus of p53 repressing its activity, but interestingly p53 activates the transcription of Mdm2.