Tumor Supressor Genes

What is tumor?

Tumor is undifferentiated or abnormal mass of cell of tissue and it may be solid or fluid filled. Tumor is also called neoplasm. A tumor doesn’t always means cancer as tumor is of two types

1. Benign Tumor i.e. non-cancerous.
2. Pre-malignant i.e. pre cancerous.
3. Malignant i.e., cancerous.

What is tumor suppressor gene?

Tumor supressor genes are the genes that regulates the growth of the cells. When these genes are functional and functioning properly then they can prevent the growth of tumor. When tumor supressor genes are altered or inactivated (due to mutation) , theuy loose ability to make the protein that controls the cell growth.

                 Tumor suppressor genes supresses cell division and growth. As a result, deletion or activation of both the alleles of such gene is tumerogenic. Therefor tumour formation due to these genes represents loss of function i.e., negative mutation and is recessive but some dominant negative mutations are also known. The two best characterized tumor supressor genes genes encode proteins  RB and p53.

Categories of tumor suppressor genes

• Caretaker genes: Maintains the integrity of genes by repairing DNA damage.
• Gatekeeper genes: Inhibits the proliferation or promotes the death of cells with damaged DNA.

RB Locus

A loss or inactivation of RB Locus is involved in retinoblastoma (a childhood disease in which tumor forms at retina) and other forms of cancer, including osteosarcomas and small cell lung cancers. This gene is located in the band of q14 of human chromosome no 13. Protein RB interacts with a variety of cellular proteins (E2F and cyclin D and E) and tumor antigens (SV40 T antigen, adenovirus E1A, etc.). RB is a nuclear protein, which is specifically phopsphorylated at the end of G1 phase by Cyclin-CDK complexes. It is dephosphorylated during mitosis, and remain in the state till it is phosphorylated again at G1/S boundary.

Unphosphorylated RB specifically binds several proteins, including E2F and Cyclin D and E. E2F is a group of transcription factor.

According to one model, Unphosphorylated RB binds E2F and thereby inactivates it.E2F group of transcription factor activate such genes whose products are essential for S-Phase.Thu unphosphorylated Rb prevents entry of cell into S- Phase and consequently, cell division.

In addition, RB-E2F complex directly repress transcription of some target genes. Phosphorylation of RB at G1/S boundary abolishes its ability to sequester E2F, which now can activate its target genes. Further, the repression of genes that are targets of RB-E2F complex is also relived. This allows the cell to enter S-phase of the cell cycle. SV40 T antigen and adenovirus E1A protein bind specifically the nonphosphorylated form of RB. This suggests that tumour antigens sequester nonphosphorylated RB by binding to it; this leaves the cellular proteins like E2F free to activate cell division. A loss of both the alleles of RB gene will have the same effect. It may be noted that certain other proteins are involved in the progression of cells from G1 to S phase.

P53 Gene

Gene p53 is the most important tumour suppressor gene; it is involved in more than half of all human cancers. This gene encodes a nuclear phosphoprotein, which was originally discovered in SV40-transformed cells where it occurs in association with T antigen. Introduction of cloned p53 gene immortalizes cells, and transformed cells or lines derived from tumours show a large increase in the amount of p53 protein. In view of this, p53 was initially classified as an oncogene. But all transforming forms of p53 gene are mutants, which function as dominant negative mutants. Protein p53 (wild type) seems to be involved in a common control of cell proliferation: normal cells presumably have the capacity for unlimited growth, which is restrained by p53.Protein p53 performs several activities as follows: (1) it binds to DNA, and recognizes an interrupted 10 base pair motif, (2) it activates transcription of genes whose promoters have multiple copies of this 10 bp motif, and (3).The C-terminal domain of p53 binds to damaged DNA in short (<40 bp) single-stranded regions. If the cell with DNA damage is in G1, it is blocked in G1; when DNA damage is repaired, the cell may enter S phase. But if the cell with DNA damage is committed to division, p53 triggers apoptosis or programmed cell death. Other factors may also affect the outcome of p53 action in response to DNA damage.The various roles of p53 may be divided into the following three groups:

01. Cell cycle arrest in G1

02. Apoptosis

03. Prevention of Genome instability.

               Binding of p53 to damaged DNA somehow activates the DNA binding and transcription activation domains of p53, which now leaves the site of damage and activates the target genes. Arrest of cell cycle results from activation of transcription of p21, which is a cell cycle inhibitor. Protein p53, following its activation by DNA damage , activated apoptosis. This may involves activation of mitochondria to trigger its apoptotic function or activation of cell surface receptors that trigger apoptosis. Finally prevention of genome instability is initiated by activation of transcription of GADD45, which encodes a DNA repair protein GADD45.This repair protein is also activated by other repair pathways that respond to irradiation damage.The level of p53 is regulated by an interaction between p53 and cellular oncoprotein Mdm2. Protein Mdm2 inhibits p53 activity , while p53 induces transcription of Mdm2.Therefore, an increase in p53 level induces transcription of Mdm2. This result in an increase in Mdm2 Level, which inhibits p53 activity.

This interaction maintains a low level of both proteins in normal cells. Binding of Mdm2 makes p53 the target of protein degradation apparatus; Mdm2 also inhibits transcription activation by p53. There is eveidence from transgenic mice that an increased activity of p53 promotes ageing; this also emphasizes a tight regulation of p53 activity.

Herditary Vs Non-inheriditary transmission of Retinoblastoma

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