what are tumor suppressor genes ?? give me detailed information !!!?

Question

dont want info frm wikipedia

Answer 1

A cell can escape from its controls when a number of genes, whose products play a role in these regulatory processes, are changed by mutations in their DNA. A cell affected in this way will then, for instance, start to proliferate too fast or it will not die when appropriate. In both instances, the number of progeny of the transformed cell is higher than that of normal cells from the same tissue. Because the descendants of the transformed cell inherit the mutations, their behavior will be as much out of line as that of their progenitor. After 30 cell divisions the clone contains 1 billion cells and weighs 1 gm. Another 10 cell divisions and the tumor weighs 1 kg and contains 1000 billion cells. During this process it is possible that additional mutations occur in one of the transformed cells, which may then result in a subclone of cells with a more aggressive behavior. The speed with which a transformed cell may form a tumor depends on the nature of the cell in question and how much of the regulator processes still remain active.

The genes whose products play a regulator role in cell growth, division, differentiation and death are all potential cancer genes. Many of these genes have now been implicated in the pathogenesis of brain tumors. There are three different types of cancer genes:

Oncogenes
Tumor suppressor genes
Mutator genes

Tumor suppressor genes:

The mutations that are observed in these genes all inactivate the gene. These mutations are loss-of-function mutations. This mechanism is fundamentally different from the activation of proto-oncogenes, where activation of one of the alleles can enhance the function of the corresponding protein manifold. In contrast, inactivation of one allele of a tumor suppressor genes will reduce the amount of tumor suppressor protein to 50% of the normal level, a situation with which many cells will be able to function comfortably. Only when the second allele has been lose will the situation change drastically because now the suppressor function cannot be performed any more. This is also the reason why almost all hereditary cancer syndromes are caused by tumor suppressor genes.

The position of tumor suppressor genes in the genome can be found by using linkage analysis for the hereditary tumor syndromes. In sporadic tumors deletions that remove a large part of a chromosome are often observed. Sometimes these are so large that they can be observed cytogenetically. In other cases specific polymorphic markers for a chromosome region are used.

The human genome contains numerous repeats of dinucleotides like CA. These repeats are very polymorphic in length and often five or more variations occur in the population. Thus, for any individual there is a reasonable chance that he or she carries two alleles of different length of a given repeat. These repeats can be amplified from purified DNA using the polymerase chain reaction (PCR). This will result in two DNA fragments of different length when the individual from whom the DNA was isolated is polymorphic for the repeat. The DNA fragments can be separated and visualized by gel electrophoreosis. When tumor DNA is compared to normal DNA from the same person, a loss of DNA in the tumor will result in the absence of one or the two amplified fragments on the gel. This phenomenon is called ‘loss of heterozygosity’ or LOH. Regions that consistently display such a LOH in tumor DNA probably harbor a tumor suppressor gene. By employing these mapping techniques many tumor suppressor genes have been found.

The Cell Cycle:

The cell cycle engine drives the cell through 4 sequential phases, called G1, S, G2 and M. Replication of DNA takes place in the S phase and in M the mitotic spindle separates the daughter chromosomes and the cell divides. The shortest cell cycles are those that result in the first divisions of a fertilized egg. In mammals the oocyte is considerably larger than other cells. Upon fertilization this allows cell cycles that only consist of S and M phases. Thus, with each cell division the volume of the daughter cells decreases. Once the cells in the embryo have reached a normal size it is necessary to increase the length of the cycle to allow the cell to grow and double its volume before the next division. The cell cycle from that stage on also encompasses the G1 and G2 phases. In addition, a cell can retract itself from the cycle and enter a quiescent stage also called the G0 phase. This possibility exists early in the G1 phase.

The cell cycle is regulated by an ordered activation of complexes between proteins called cylins and cyclin dependent kinases or CDKs. These complexes regulate processes like DNA synthesis, nuclear envelope breakdown, spindle assembly and chromosome segregation and mitosis. Cyclin-CDKs can only form a complex when the kinase subunit is phosphorylated. Sequential activation of different cyclin-CDK complexes occurs via phosphorylation and by induction of transcription of the components. Negative regulation occurs through cyclin-dependent kinase inhibitors (CDKIs) and degradation of the proteins. Some of the proteins involved have extremely short half-lives, which facilitates a rapid adaptation of the cell cycle engine to altered circumstances.

Complexes between a cyclin D and CDK4 or CDK6 (which complex is employed depends on the nature of the cell) are activated by mitogenic stimuli reaching the nucleus of the cell through the signal transduction pathways. This causes the cell to move from G0 to G1. In quiescent cells no D type cyclin is apparent and levels of these cyclins drop immediately in any phase of the cycle when growth factors are removed. In lymphomas the gene is overexpressed by specific chromosomal translocations. The CDK4 gene is amplified in many gliomas and glioblastomas. After cyclin D, the next cyclin to be activated is cyclin E. Its activity peaks in the later stages of G1. Cyclin E associates with CDK2. Late in G1, cyclin A-CDK2 is activated and this complex is thought to be involved in the up-regulation of proteins that participate in DNA synthesis. Transit from S to M is facilitated by the cyclin B-CDC2 complex.

The cell cycle knows a number of checkpoints. First the G0/G1 transition depends on the availability of growth factors. In the first two-thirds of G1, growth factors are continuously required or else the cycle stops and the cell returns to G0 or will die by activating its apoptotic suicide program. If the first two-thirds of G1 proceed according to plan the cell encounters the R (restriction) point where it will decide whether to continue towards the S phase. After this point growth factors are no longer required and the cell is committed to proceed to S. At the transitions from G1 to S and G2/M the cell checks whether all DNA has been replicated completely. If DNA damage is detected, the cell cycle may arrest at these points to allow DNA repair. If the damage is substantial, the cell may decide to activate its suicide pathway.

The C1/S cell cycle checkpoint:

There are two moments in the cell cycle when a cell checks the status of its DNA. One of these is at the end of G1. At this point, the cell has to choose between two possibilities. When the damage is extensive, TP53 will induce the cell to use its suicide pathway. If the damage is such that repair is possible, TP53 stops the cell cycle at this point, a phenomenon that is called G1 arrest. Cells which lack functional TP53 are unable to arrest the cycle at this point when DNA damage is inflicted. Upon DNA damage a conformational change is induced in the TP53 protein which increases its half life and upregulates its functions as a transcription factor. G1 arrest by TP53 is mediated, at least in part, by the cyclin dependent kinase inhibitor CDKN1A, a protein of 21 kD. The transcription of the CDKN1A gene is induced by TP53.

CDKN1A binds to CDK2 and CDK4 and inhibits the phosphorylation of their targets. DNA repair enzymes start to remove the DNA lesions and once this is finished and the DNA is repaired, the levels of TP53 will drop and the CDKN1A gene will be shut off and the cell cycle can continue. Apart from inhibiting the cell cycle via binding to cyclin/CDK, CDKN1A also binds to PCNA, a protein that is essential for DNA replication and whose transcription is activated by TP53. It is possible that not G1 arrest, but the inability of TP53 negative cell to undergo DNA damage-induced apoptosis is more important for TP53 related carcinogenesis and this function of TP53 seems to be independent of CDKN1A.

The G2/M cell and spindle checkpoints:

The transition between G2 and M is prevented when DNA damage and/or incompletely replicated DNA are detected. This transition of G2 to M is brought about by the phosphatase CDC25. In the G2 phase of the cycle CDC2 is phosphorylated on threonine 161 by CAK (cyclin activating kinase) and on tyrosine 15 by the WEE1-like kinases. The resulting phosphorylated cyclin B-CDC2 complex is inactive and can only be activated by dephosphorylation of tyrosine 15 by CDC25.

It is also possible that TP53 also plays a role at this cell cycle checkpoint, but the evidence at this point is not conclusive. For instance, the concentration of TP53 artificially to levels that are comparable to those that are induced by DNA damage, arrested cells in G1, but a fraction of the cells also arrested at G2/M.

In addition to the G2/M checkpoint, a spindle checkpoint seems to exist in the M phase and TP53 probably also plays a role there. Evidence for this comes from the observation that when TP53 negative mouse fibroblasts are treated with spindle inhibitors, this results in ongoing DNA synthesis without segregation of the chromosomes and the subsequent creation of polyploid cells. Thus TP53 may be important for maintenance of the diploid status of the cells. The fact that many tumor cells are polyploid may therefore be due to mutations in the TP53 gene.

Answer 2

Some genes suppress tumor formation.
Their protein product inhibits mitosis.
When mutated, the mutant allele behaves as a recessive; that is, as long as the cell contains one normal allele, tumor suppression continues. (Oncogenes, by contrast, behave as dominants; one mutant, or overly-active, allele can predispose the cell to tumor formation).

Answer 3

I personaly think that you are wrong

Answer 4

no

Answer 5

look here;http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/T/TumorSuppressorGenes.htmlhttp://www.cancer.org/docroot/ETO/content/ETO_1_4x_oncogenes_and_tumor_suppressor_genes.asp