BASIC MECHANISMS OF CELL GROWTH TRANSFORMATION

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Cancer is a genetic disease: In order for cells to start dividing uncontrollably, genes that regulate cell growth must be damaged.

Genetic damage found in cancer cells is of two types:

1. Dominant and the genes have been termed proto-oncogenes. Proto-oncogenes, which are normal and functional cellular genes, promote cell growth and mitosis, code for secreted proteins, transmembrane proteins, cytoplsmic proteins or nuclear proteins; all have potency to induce cancer or suppress cancer. 

Proto-oncogenes promote cell growth in a variety of ways. Many can produce hormones, "chemical messengers" between cells that encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. Some are responsible for the signal transduction system and signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. They often produce mitogens, or are involved in transcription of DNA in protein synthesis, which create the proteins and enzymes is responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes can modify their expression and function, increasing the amount or activity of the product protein. When this happens, they become oncogenes, and, thus, cells have a higher chance to divide excessively and uncontrollably.

Thus, oncogenes are the activated form of proto-oncogenes, i.e., proto-oncogenes are the normal version of genes which when activated form oncogenes.

The distinction between the terms proto-oncogene and oncogene relates to the activity of the protein product of the gene. A proto-oncogene is a gene whose protein product has the capacity to induce cellular transformation given it sustains some genetic insult. An oncogene is a gene that has sustained some genetic damage and, therefore, produces a protein capable of cellular transformation.

The process of activation of proto-oncogenes to oncogenes can include retroviral transduction or retroviral integration (see below), point mutations, insertion mutations, gene amplification, chromosomal translocation and/or protein-protein interactions.

Proto-oncogenes can be classified into many different groups based upon their normal function within cells or based upon sequence homology to other known proteins. As predicted, proto-oncogenes have been identified at all levels of the various signal transduction cascades that control cell growth, proliferation and differentiation.

2. Recessive and the genes variously termed tumor suppressors, growth suppressors, recessive oncogenes or anti-oncogenes.

Tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. Many tumor suppressor genes effect signal transduction pathways which regulate apoptosis, also known as "programmed cell death". Typically, a series of several mutations to these genes is required before a normal cell transforms into a cancer cell. Mutations to these genes provide the signals for tumor cells to start dividing uncontrollably.

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.

Among all tumor suppressors p53 is the most powerful regulator that acts at various stages of cell cycle to suppress tumor induction.  P53 is named after its molecular weight 53Kd; it is Phospho-protein always found in the nucleus, becomes tetramer and acts.  If one of the tetramer is damaged, the tetramer fails to function, which amounts to loss of function with characteristic dominant negative mutation.  It is half-life is very short-20 minutes.  Its concentration in normal cells is low, but when cell suffers damage at DNA level the protein gets activated and become stable and also it concentration increases.  If there is damage to DNA, p53 blocks cell progression beyond G1 stage. If the damage is beyond repair, p53 induces apoptosis.

P53 has many domains each of which has specific function; very rarely one finds a protein contains so many domains and so many functions.  That is one of the reasons why animal systems including human beings, with mutations in p53, are generally susceptible to cancer.  This protein acts like a vanguard among others against tumorigenesis.  More than 50% of the cancer patients have p53 disfunctioned or disfunctioning p53 in mammary carcinoma.  Mice homozygous recessive for p53 survive only for few months and 100% die, but mice with heterozygous live little longer and they are as good as dead, but statistics show 80% of them die.

When p53 suffers mutation in one or the other form, cell at any time can to be transformed into tumor with other mutated cancer causing genes.

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.

Multiple mutations: In general, mutations in both types of genes are required for cancer to occur. For example, a mutation limited to one oncogene would be suppressed by normal mitosis control and tumor suppressor genes. A mutation to only one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes, and enough tumor suppressor genes deactivated or damaged, that the signals for cell growth overwhelm the signals to regulate it, that cell growth quickly spirals out of control. Often, because these genes regulate the processes that prevent most damage to genes themselves, the rate of mutations increases as one gets older, because DNA damage forms a feedback loop.