ACHARIYA ARTS AND SCIENCE COLLEGE(AFFILATED TO PONDICHERRY UNIVERSITY)

DEPARTMENTAL SEMINAR BIOTECHNOLOGY DEPARTMENT

TOPIC:-TUMOUR SUPPRESSOR GENE

Presentation by Gopi Krishna Giri

Tumor Suppressor Genes

Guided by

Dr.DE.Salamun

TUMOR

A tumor, also known as a neoplasm, is an abnormal mass of tissue which may be solid or fluid-filled.

A tumor does not mean cancer - tumors can be benign (not cancerous), pre-malignant (pre-cancerous), or malignant (cancerous).

CANCER

The name for diseases in which the body's cells become abnormal and divide without control.

They may spread through the bloodstream

and lymphatic system to other parts of the body.

WHAT IS TUMOR SUPPRESSOR GENE ?

Tumor suppressor genes are genes that regulate the growth of cells. When these genes are functioning properly, they can prevent and inhibit the growth of tumors.

When tumor suppressor genes are altered or inactivated (due to a mutation), they lose the ability to make a protein that controls cell growth.

Categories of tumor suppressor genes

Caretaker genes:Maintain the integrity of the genome by repairing

DNA damage

Gatekeeper genes:Inhibit the proliferation or promote the death of

cells with damaged DNA

Tumor suppressor genes: functional categories and tumor association

Category Gene Function Tumor susceptibility if germ line mutation

Comments

Gatekeepers p53 Transcription factor

Li-Fraumeni syndrome Also mutated in 50% of human cancers

Rb1 Transcriptional regulator

Familial retinoblastoma

Often mutated in other cancers

APC Regulates β-catenin function

Familial adenomatus polyposis

Often mutated in sporadic colorectal cancers

Caretakers BRCA1 DNA repair Breast and ovarian cancer

Rarely mutated in sporadic breast cancers

BRCA2 DNA repair Breast cancer(female and male)

MSH2MLH1

DNA mismatch repair

Hereditary non-polyposis colorectal cancer

Mutation permits further mutations

Retinoblastoma(Rb) gene

First phenotypic cancer suppressor gene to be discovered

Responsible for retinoblastoma, a malignant tumor of retina, a rare childhood tumor

60% are sporadic (non-inherited), remaining ones are familial

Two-hit hypothesisTo account for the sporadic and familial

occurrence of retinoblastoma, Knudson, in 1974– Two mutations(hits) are required with Rb gene ,

located 13q14, for the development of retinoblastoma

– In familial cases, children inherit a defective copy of Rb gene, the other copy is normal. Retinoblastoma develops when the normal copy undergo somatic mutation

Recessive disorder, Transmitted as dominant trait– In sporadic cases, both normal Rb alleles are lost by

somatic mutation in one of the retinoblasts.

The “two-hit" origin of retinoblastoma

p53 Gene

Situated at the short arm of the chromosome 1

It is also called TP53 or tumor protein codes for protein that regulate the cell cycle

Normal functions p53Repair of damaged DNA before S-phase in the

cycle by arresting the cell cycle in G1 until the damage is repaired

Apoptosis cell death if there is extensive DNA damage

p53 GeneP53 level raise in cells with sustained cell

damage, until the damage is repaired or cell undergoes apoptosis.

Prevents propagation of possibly mutated cells.

Called “the guardian of the genome”.

P53 gene

Involved directly in DNA repair

Transcriptional target gene p53R2 encodes ribonucleotide reductase important for DNA replication & repair

Interacts with AP endonuclease & DNA polymerase

MECHANISM OF P53

p53 Gene

P53 can lost its function by:Non-sense mutation or mis-sense mutation

Complex of normal p53 and mutant p53 inactivating the function of normal allele

Binding of normal p53 to viral oncoproteins

Role of p53 in cells with damaged DNA

Li- Fraumeni syndrome

Li- Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome.

This means that a person who has LFS will have an increased risk of developing cancer.

Li- Fraumeni syndromeCommon type of cancer found in LFS- bone

cancer,breast cancer, brain cancer

Affected individuals Carry germ line mutation in one p53 allele, but tumors display mutation at both alleles

Another example of two-hit hypothesis

APC Gene

Implicated in familial adenomatous polyposis coli and most sporadic colorectal cancers

β-catenin- is a dual function protein, tissue formation & helps to control the acticity(expression) of other gene & promote cell growth & division.

In humans, β-catenin is encoded by the CTNNB1 gene

APC Gene

Excess of β-catenin promotes uncontrolled growth & division of cells

APC binds to and inhibits the function of β-catenin

Mutant APC is unable bind β-catenin to down regulate its activity & produce desmoid tumor

WT-1 gene

WT1(Wilms tumor 1)gene codes for protein responsible development of the kidney and gonads

It codes for a DNA-binding protein that represses transcription of PDGF and IGF-I which promotes growth

WT-1 gene

WT1 protein regulates the activity of other genes by binding to specific regions of DNA that is why it is also called transcription factor

It also causes self-destruction of cells (apoptosis)

Loss of WT-1 gene expression also occur in many breast cancers

NF-1 gene

Germ line mutation in type 1 neurofibromatosis (NF)

Encode neurofibromin, a negative regulator of ras gene

Inactivation of NF-1 permits unopposed ras, thereby promotes cell growth

P15 and p16 genes

Inactivation identified primarily in breast, pancreas and prostate tumors.

The gene products are cdk inhibitors and serve as the negative regulators of the cell cycle

BRCA1 and BRCA2 genes

Breast (BR) cancer (CA) susceptibility genes, also incriminated in some ovarian cancers

Involved in G1 check pointBlock entry of cell into S phase, particularly by

inducing CDK inhibitor p21Promote DNA repair by binding to RAD51

Conclusion

suppression of genes that are essential for the continuing of the cell cycle.

If the damage cannot be repaired, promote apoptosis.

Produce protein responsible for inhibition of metastasis

Inactivation of tumour suppressor gene causes tumour

References www.bioinformatics.org/p53/introduction.html.

www.ncbi.nlm.nih.gov/podmed/12060387

www.nlm.nih.gov/geneAPC

www.nlm.nih.gov/gene/NF1

www.wikipedia.org/wiki/Neoplasm