TUMOR SUPPRESSOR GENES



INTRODUCTION

Tumor suppressor genes and oncogenes are important regulatory genes which encode proteins regulating transitions in and out of the cell cycle and which also have a role in the gateway to terminal differentiation. Defects in tumor suppressor genes and oncogenes result in uncontrolled cell division, which leads to cancer.

Oncogenes are mutated proto-oncogenes that have a role in malignancy of tumors and most frequently regulate cell cycle re-entry. Gain-of-function mutations result in transformation of proto-oncogenes into dominant oncogenes.Tumor suppressor genes encode proteins proteins that suppress cell growth and most frequently result in exit from the cell cycle. Loss-of-function mutations in tumor suppressor genes result in tumor malignancy and can account for hereditary cancers.

For tumor suppressor genes to be inactivated either deletion of one allele is required resulting in a loss of heterozygosity, or somatic deletion of both of the alleles is required resulting in a complete loss of homozygosity. Tumor suppressor genes can also be inactivated by hypermethylation of the gene resulting in promoter suppression so that genes can not be transcribed further.

TUMOR SUPPRESSOR GENES


P16

CKI p16 is an important tumor suppressor gene, defects in which are associated with cancer. p16 is an important CKI and a tumor suppressor gene encoded on the 9p21 region of the human genome.

The classic role of p16/INK4A/CDKN2A is to check the cell cycle in early G1 phase and inhibit further transition of the cell cycle from G1 to S phase as a component of a multi-protein regulatory complex.

The INK4a/ARF locus is of critical importance in tumor suppression. This locus is inactivated in about 40% of  human cancers, a frequency only comparable with that of p53 inactivation. The INK4a/ARF locus encodes two tumor suppressors, p16INK4a and p14ARF/p19ARF (p14 when referred to the human protein and p19 when referred to the mouse protein).

Protein p16INK4a inhibits the activity of the CDK4,6/cycD kinases, thus contributing to the maintenance of the active, growth suppressive from of the retinoblastoma family of proteins.

TUMOR SUPPRESSOR GENES
Image source- https://ar.iiarjournals.org/content/35/8/4397

P53

  • P53 is a tumor suppresor genes, guardian of genome, nuclear protein.
  • Cell cycle arrest during G1/S and G2/M arrest in cells with damage DNA: mediated by p21, a cdk inhibitor that is essential for progression from G1 to S phase.
  • Apoptosis- If the DNA repair system fails to correct the damaged DNA, P53 trigger such cells to undergo apoptosis. Mediators are pro-apoptotic protein like Bax, Apaf-1, PUMA and NOXA.

NORMAL P53

When cellular damage occurs. P53 arrests the cell cycle until the damage is repaired. If damage is repaired. If damage cannot be repaired, apoptosis occurs.  

MUTATED P53

When cellular damage  occurs. Mutated p53 does not arrest the cell cycle. The damaged cell continues to divide, which may result in cancer.             

Mutations in the p53 gene are found in a greater percentage of tumors than any other gene mutation . The situation with the p53 gene is complicated by the fact that mutation can result in

  1. The loss of tumor suppressor function
  2. Oncogene activity including a dominant negative effect which overides the influence of the wild type gene
TUMOR SUPPRESSOR GENES
Image source- https://en.m.wikipedia.org/wiki/P53

Rb (RETINOBLASTOMA)

  • ¬†Retinoblastoma is an eye tumor of young children that occurs in a hereditary or a sporadic form. Deletions have been found in chromosome 13 associated with retinoblastoma.
  • Inheritance of one gene puts the individual at greater risk. A somatic mutation in the other Rb gene will cause cancer whereas somatic mutations in two genes would be required in the normal individual.
  • The Rb gene codes for a 105kd protein. When hypophosphorylated p105 Rb exerts a growth restraining influence in the G1 phase of the cell cycle.
  • Phosphorylation of the Rb protein inhibits its growth regulatory action. The Rb protein is a substrate for phosphorylation by cyclin- dependent kinases.
  • ¬†Hypophosphorylated Rb protein binds less tightly to the nucleus and less tightly to the E2F transcription factor which activates some genes for the cell cycle progression. In the normal cell cycle, Rb becomes hyperphosphorylated at the G1/S transition and is released from the E2F transcription factor. The Rb protein can also bind specific DNA sequences and serve as a transcriptional regulator.
TUMOR SUPPRESSOR GENES
Image source- https://www.nature.com/scitable/content/the-p53-and-rb-tumour-suppressor-pathways-14267125/

MORE EXAMPLES OF TUMOR SUPPRESSOR GENES

GENECANCER TYPE
APCColoncancer
BRCA1Breast cancer
BRCA2Breast cancer
DCCColon cancer
NF1Neurofibromas
NF2Schwannomas and Meningiomas
P53Many types
PTENGliomas
RbRetinoblastoma
VHLKidney and other tumors
WT1Wilms tumor

CONCLUSION

There are tumor suppressing activities in normal cells. This concept is provided by chromosomal deletions associated with some malignancies. There can be hereditary and sporadic defects for the tumor suppressor genes. Tumor suppressor gene list consist of p16, APC, p53, Rb, DCC, BRCA1,2, etc.

p16/ INK4A/CDKN2Anis an important tumor suppressor gene, which is required for the control of unregulated cell growth in many and perhaps most cell types. The INK4A locus is also unique in eukaryotes. Despite these constraints, mutation of p16 is second only to p53 in mutation frequency in a wide range of tumors.


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