12. Tumor-suppressor genes Tumor-suppressor genes, function like brakes, keep cell numbers down, either by inhibiting progress through the cell cycle and thereby preventing cell birth, or by promoting programmed cell death (also called apoptosis). When cellular tumor suppressor genes are rendered non-functional through mutation, the cell becomes malignant. Examples are the gene encoding the retinoblastoma protein (Rb), inactivated in retinoblastomas, p53, and p16INK4a, which inhibits cyclin-dependent kinases and is inactivated in many different tumors.

13. Oncogenes Oncogenes stimulate appropriate cell growth under normal conditions, as required for the continued turnover and replenishment of the skin, gastrointestinal tract and blood, for example. Cells with mutant oncogenes continue to grow (or refuse to die) even when they are receiving no growth signals. Examples are Ras, activated in pancreatic and colon cancers, and Bcl-2, activated in lymphoid tumours. Amplification of oncogenes (more than their normal gene copy number) is also found in cancer: MDM2 is amplified in liposarcomas.

14. Roles of p53 in apoptosis 1.p53 induces apoptosis through transcriptional activation of proapoptotic genes, such as Puma, Noxa, p53AIP1, Bax, Apaf-1 etc. 2.It can also directly induce apoptosis by localizing to mitochondria via interaction with Bcl-2 family protein Bcl-xL and facilitating Bax oligomerization Reading: Vousden and Lu: Nature Reviews Cancer, 2002, 2:594-604.

15. Tumor Suppressor p53 First identified as a protein associated with viral oncogenes Mutated/inactivated in a majority of human cancers Integrates numerous signals that control cell life and death A common denominator in human cancer Understanding functions and regulation of p53 is of great importance in cancer biology and cancer therapy

16. p53 and of apoptosis Ref: Mol. Cell, 2003, 11(3):552-4

18. The p53 pathways

19. p53 is a sequence-specific DNA binding protein 1.p53 central core-domain interacts directly with DNA 2.p53 binding sites consist of four copies of the pentamer consensus sequence PuPuPuC(A/T). The pentamers are oriented in alternating directions. A short stretch of sequence up to 13 bp may be inserted between the pairs of pentamers. The p53 target genes in the human genome usually carry the consensus sequence. 3. Amino acid residues in the core-domain that are critical for DNA-binding are among the “hot-spots” of tumor- derived p53 mutations, attesting to the importance of DNA-binding for p53’s tumor suppression function.

20. p53 and apoptosis Apaf-1 p53AIP1

21. 1.p53 mediates apoptosis in response to DNA damage, oncogene expression (adenovirus E1A, myc etc.), or withdrawal of growth factors 2. Overexpression wild-type of p53 leads to apoptosis 3. p53 can induce the expression of proapoptotic genes, such as Bax (ref Cell, 80:293) and p53AIP1 (ref: Cell, 102:849) p53 in apoptosis

22. Suppress oncogene-induced transformation Inhibit tumor growth and progression Remove cells with severe DNA damage Effectiveness of cancer chemotheraphy correlates with the ability to induce p53-dependent apoptotic response Physiological relevance of p53- induced apoptosis

23. p53 in DNA repair and apoptosis Ref: Bensaad & Vousden, Nature Med, 2005 ROS: reactive oxygen species