tumor suppressor gene, prb, p53 gene

Introduction
History
Tumor suppressor gene- pRB
- RB gene
- Role of RB in regulation of cell cycle
- Tumor associated with RB gene mutation
Tumor suppressor gene- p53
- What is p53 gene?
- Function of p53 gene
- How it regulates cell cycle
- What happen if p53 gene inactivated
- Cancer associated with p53 mutation
- Conclusion
- References

1. tumor suppressor Gene Action of pRB and p53 1 By KAUSHAL KUMAR SAHU Assistant Professor (Ad Hoc) Department of Biotechnology Govt. Digvijay Autonomous P. G. College Raj-Nandgaon ( C. G. )

2. CONTENTS Introduction History Tumor suppressor gene- pRB - RB gene - Role of RB in regulation of cell cycle - Tumor associated with RB gene mutation Tumor suppressor gene- p53 - What is p53 gene? - Function of p53 gene - How it regulates cell cycle - What happen if p53 gene inactivated - Cancer associated with p53 mutation - Conclusion - References 2

3. INTRODUCTION Tumor suppressor proteins – Tumor suppressor gene act as a cell brakes; they encode proteins that restrain cell growth and prevent cells from becoming malignant. Oncogenes – Encoded proteins that promote the loss of growth control and the conversion of cell to a malignant state. 3

4. Fig- (a) Mutated tumor suppressor gene (b) Oncogenes 4

5. HISTORY The existence of such genes originally came to light from studies in the late 1960s. When normal and malignant rodent cells were fused to one another. Some of the cell hybrids formed from this type of fusion lost their malignant characteristics, suggesting that a normal cell possesses factors that can suppress the uncontrolled growth of a cancer cell. 5

6. Tumor suppressor gene - pRB Tumor suppressor protein is a product of tumor suppressor gene. It regulate cell growth by applying brake to cell proliferation (Growth inhibition). Failure to growth inhibition cause carcinogenesis. And loss of function of this pRB gene is a key events in carcinogenesis. 6

7. Loss Of Heterozygosity – Both normal alleles of normal function of tumor suppressor gene tumor suppressor gene. One allele active normal function of (normal) and another tumor suppressor abnormal (inactive) gene. (Heterozygous state) Both are abnormal loss of function of tumor (inactive) suppressor gene. (loss of heterozygosity ) cause mutation 7

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9. RB gene 1 st discovered tumor suppressor gene. RB stand for Retinoblastoma. Retinoblastoma is a human childhood disease, involving a tumor of retina. It occur both as a heritable trait and sporadically. It is often associated with deletion of band q14 of chromosome 13. Retinoblastoma arises when both copies of RB gene are inactivated. 9

10. Fig- (a) Sporadic case (b) Inherited case 10

11. Role of RB in regulation of cell cycle The protein encoded by the RB gene, pRB, helps regulate the passage of cells from the G1 stage of the cell cycle into S phase. From G1 to S is a time of commitment for the cell; once a cell enters S phase, it invariably proceeds through the remainder of the cell cycle and into mitosis. The transition from G1 to S is accompanied by the activation of many different genes that encode proteins ranging from DNA polymerases to cyclins and histones. 11

12. Among the transcription factors involved in activating genes required for S phase activities are members of the E2F family of transcription factors, which are key targets of pRB. During G1, the unphosphorylated pRB is bound to the E2F protein. The E2F–pRB complex binds to regulatory sites in the promoter regions involved in cell cycle progression, acting as a transcriptional repressor that blocks gene expression. At the end of G1 Activation of the cyclin -dependent kinase ( Cdk ) leads to the phosphorylation of pRB, which can no longer bind the E2F protein. 12

13. loss of the bound pRB converts the DNA-bound E2F into a transcriptional activator, leading to expression of the genes being regulated. The mRNA is translated into protein that are required for the progression of cells from G1 into S phase of the cell cycle. NOTE- Some DNA tumor viruses (including adenoviruses, human papilloma virus, and SV40) encode a protein that binds to pRB, blocking its ability to bind to E2F. 13

14. Fig- Role of pRB in controlling transcription 14

15. Tumor associated with RB gene mutation Retinoblastoma. Osteosarcoma . Breast cancer. Lung cancer . 15

16. Tumor suppressor gene - p53 The most important tumor suppressor is p53 (named for its molecular size) 53 kDa . It is located on band p13 of chromosome 17. Also called ‘’ Guardian of the Genome’’. In 1990, p53 was recognized as the tumor-suppressor gene. Its activity stop formation of tumor. Mutation in p53 is the cause of Li- Fraumeni syndrome, which is rare form of inherited cancer. All normal cell have low level of p53. 16

17. Function of p53 DNA repairing. Apoptosis. Regulation of cell cycle. Prevent neoplastic transformation either by cell cycle arrest or by triggering apoptosis. 17

18. DNA damage Trigger the expression of p53 Increase level of p53 Prevent cell from entering to S phase It mean arrest of cell cycle at G1 phase And p53 induce DNA repair gene DNA repair DNA not repair Degrade p53 permanent arrest apoptosis Cell cycle continue 18

19. Fig- DNA of cell become damage 19

20. How it regulates cell cycle Activated p53 encodes a protein called p21 that inhibits the cyclin -dependent kinase that normally drives a cell through the G1 checkpoint. As the level of p53 rises in the damaged G1 cell, expression of the p21 gene is activated, and progression through the cell cycle is arrested. This gives the cell time to repair the genetic damage before it initiates DNA replication . 20

21. Cell cycle arrest is not the only way that p53 protects an organism from developing cancer. Alternatively, p53 can direct a genetically damaged cell along a pathway that leads to death by apoptosis. Including the activation of expression of the BAX gene, whose encoded product ( Bax ) initiates apoptosis . 21

22. Fig- p53 activity on damage DNA 22

23. What happen if p53 gene inactivated If both copies of the p53 gene are inactivated. 23

24. Cancer associated with p53 mutation Liver cancer. Lung cancer. Breast cancer. Ovarian cancer . 24

25. CONCLUSION So, pRB and p53 tumor suppressor gene are very important to inhibit the growth of tumor or called malignant cancer. 25

26. REFERENCES 26