The document discusses several studies on the p53 tumor suppressor protein and its role in cancer development. It summarizes that p53 is stabilized in response to DNA damage, activating kinases and the ARF protein. Stabilized p53 can then act as a transcription factor to block angiogenesis and tumor growth. The document also reviews how viral oncogenes can inactivate p53 through binding proteins like MDM2, contributing to cancer development.

2. p53 Lu et al., (2009) Nature Rev Cancer 9: 758-762

8. Rol BRCA1 en 2 in DNA schade bron: Google/Internet....

14. p53 and p19 ARF From Moll and Petrenko, Mol. Cancer Res. 1, 2003, 1001-1008 ARF=human p14 ARF =mouse p19 ARF ARF binds mdm2 protein nucleolus

17. Surfing the p53 network Vogelstein et al., Nature 2000, 408: 307-310 Lack of p53 function; p53 functions only in nucleus Breast, neuroblastoma Mislocalization of p53 to cytoplasm Failure to inhibit MDM2 and to control p53 degradation Breast, brain, lung, tumours in which p53 itself is not mutated Deletion of the p14 ARF gene Viral proteins bind and inactivate p53 Cervix, liver, lymphomas Viral infection Extra mdm2 stimulates degradation of p53 Sarcomas, brain Multiplication of the MDM2 gene Prevents formation of tetramers of p53 Occasional tumours at many different sites Deletion of carboxy-terminal domain Prevents p53 from binding DNA and to activate genes Colon, pancreas, lung, bladder, many others Amino acid mutation in DNA- binding domain Effect of inactivation Typical tumours Mechanism of p53 inactivation

18. Viral oncogenes and the p53 network Vogelstein et al., Nature 2000, 408: 307-310 p14 ARF protein MDM2 p53 Viral p53- inactivating proteins E2F1 E2F1 Rb Rb Viral Rb-binding proteins Polager &Ginsberg Nature Rev Cancer Oct 2009

19. Summary p53 Cancer: three birds with one stone Toledo & Bardot (2009): Nature 460, 466-467 DNA breaks ATM kinase DNA- dependent kinase ATR kinase p14 ARF UV, stress Oncogenes p53 stabilisation Block angiogenesis

20. Summary p53 Cancer: three birds with one stone Toledo & Bardot (2009): Nature 460, 466-467 DNA breaks ATM kinase DNA- dependent kinase ATR kinase p14 ARF UV, stress Oncogenes p53 stabilisation Block angiogenesis

21. Summary p53 Cancer: three birds with one stone Toledo & Bardot (2009): Nature 460, 466-467 DNA breaks ATM kinase DNA- dependent kinase ATR kinase p14 ARF UV, stress Oncogenes p53 stabilisation Block angiogenesis