EUKARYOTIC CELL SIGNALING VII Abnormal Signaling in Cancer Signaling to p53 Dr. Ke Shuai Office: 9-240M Factor Tel: X

Cancer Development Multi-hit models of cancer induction: the development of a cancer requires several mutations. 1) The incidence of most types of human cancers increases markedly with age. 2) Most mutations in human tumors are somatic and inherited mutations increase cancer risk. 3) Cooperative effects by mutations contribute to cancer development.

Oncogenes and Tumor Suppressor Genes 1) Oncogenes: altered cell growth promoting regulatory genes, resulting in the overproduction or increased activity of these proteins. 2) Tumor-suppressor genes: encode proteins that inhibit the progression of tumors. 3) Oncogenes alone are not sufficient to cause cancer. Inactivation of tumor suppressors is a major event leading to the development of cancer.

Genetic Alternations Mutations: point mutations Deletions: the removal of a segment of DNA Translocations: chromosomal translocation that leads to the inappropriate expression of the gene or the generation of a fusion gene. Amplification: localized reduplication (gene amplification) of a DNA segment, leading to overexpression of the encoded proteins.

Induction of cancer by alternations in several types of proteins involved in cell growth control

Signaling to p53 P53 protein becomes stabilized in response to DNA damage and stress signals.

The structure of p53

Mechanisms for p53 Activation 1. Phosphorylation 2. MDM2 dissociation 3. Recruitment of co-activators 4. Acetylation 5. Dephosphorylation and binding to adaptor protein

The p53-Mdm2 Autoregulatory Loop

Oncogene and DNA Damage Activate p53 by Distinct Mechanisms

The regulation of p53 functions

Smoking is associated with p53 mutation in oral and lung cancers Inactivation of p53 in cancer Vertical lines represent the frequency at which mutations are found at each residue in various human tumors. P53 is stabilized by phosphorylation. MDM2 protein binds at the indicated site and represses transcriptional activity of p53. P53 is also inhibited by viral proteins such as E6 from human papillomavirus and E1b from adenovirus.

Cancer Therapies 1). Conventional cancer therapies: surgery, radiation, chemotherapy 2). Potential new therapies: gene therapy; specific inhibitors (e.g. of tyrosine kinase); antibodies (e.g. anti-EGFR antibodies). 3). Early diagnosis: offers better treatment, cosmetic and functional outcome, and survival.