分子生物學(xué)英文課件：oncogene

1、Oncogenes and Tumor Suppressor Genes,Section I Oncogenes Oncogenes are genes whose products have the ability to transform eukaryotic cells in culture or to induce cancer in animals, including virus oncogene（v-onc）and cellular oncogene (c-onc). Most oncogene are mutant forms of normal genes （ proto-

2、onc） involved in the control of cell growth or division.,V oncogene A nucleic acid sequence in a virus responsible for the oncogenicity of the virus; it is derived from the cellular proto-oncogene and acquired from the host by recombination.,Retroviral life cycle,Retroviral oncogenes (partial list)

3、V-onc Prototype retrovirus src Rous sarcoma virus myc Avian myelocytomatosis virus erb A, erb B Avian erythroblastosis virus myb Avian myeloblastosis virus H-ras Harvey rat sarcoma virus K-ras Kirsten murine sarcoma virus abl Abelson murine leukemia virus fes Feline sarcoma virus sis Simian sarcoma

4、virus,Pro-oncogene A normal gene that has the potential to become an oncogene.,Cellular oncogene a proto-oncogene that has been activated within the host so that oncogenicity results.,Characteristics They distribute widely from yeast to human beings; They have been highly conserved over eons of evol

5、utionary time; Low expression level, basic to animal life, their products participate in cellular growth-controlling pathways; When inappropriately activated, these genes can lead to a fault in growth control and contribute to the development of cancer.,Products and functions of pro-oncogenes Growth

6、 factors Transmembrane receptor for growth factors Intracellular signal transducer: intracellular tyrosine kinases, Ser/Thr kinases, etc. Transcription factors,C-Erb-B,C-ras,raf,src,C-myc,C-sis,C-erb-A,Mechanism of proto-oncogene activation Promoter insertion and enhancer insertion Chromosomal (gene

7、) translocation (染色體易位) and rearrangement Gene amplification Point mutations,Promoter/enhancer insertion,When retrovirus genome integrate into cell chromosome, the strong promoter / enhancer in the retrovirus LTR (long terminal repeat) can activate some proto-oncogene and induce its overexpression.,

8、Chromosome translocation,Chromosome distortion, break or translocation often occur in tumor cells. Chromosome translocation is that one part of one chromosome exchange with another chromosome. Chromosome translocation can cause changes in gene structure and gene expression. Proto-oncogene can be act

9、ivated and overexpressed if it is close to a strong promoter/enhancer.,Burkitts lymphoma (Burkitts 淋巴瘤) is a solid tumor of B lymphocytes,It involves a reciprocal translocation (相互易位 )that has moved the proto-oncogene c-myc from its normal position on chromosome 8 to a location close to the enhancer

10、s of the antibody heavy chain genes on chromosome 14. This leads to overexpression of the myc transcription factor.,Gene amplification,Proto-oncogenes belong to single-copy genes. Proto-oncogenes can be amplified into 50 500 copies, and its expression level can be increased by 50500 fold.,Point muta

11、tion,Single base change one code changed one AA changed activity change Mutant protein can continuously transduce growth signal and cause cell transformation.,Proteins encoded by oncogenes,New proteins Superfluous normal proteins Abnormal proteins：devoid of important regulatory elements,Section II T

12、umor Suppressor Genes Tumor suppressor genes are genes that have a negative, suppressing effect on tumor creation and thus help to prevent formation of tumors.,The retinoblastoma (視網(wǎng)膜母細胞瘤) gene was the first tumor suppressor gene to be identified and characterized in man. Inactivation of the retinob

13、lastoma gene by mutation or deletion leads to complete failure of the function of the gene and thus to tumor formation.,Rb has 2 forms: phosphorylated Rb protein (inactive form) unphosphorylated Rb protein (active form) Function: control cell cycle The Rb gene product (RB, non-phosphorylated) intera

14、cts with a protein called E2F (transcription factor). The mutant RB is always phosphorylated and can not regulate E2F, and normal cells become cancerous.,RB has been shown to be a negative regulator of progression in the cell cycle at the G1 to S transition : 1. In G0/G1, unphosphorylated RB binds t

15、o a transcription factor (E2F), which inactivates E2F. 2. At the end of G1, RB is phosphorylated, releasing E2F. 3. Active E2F stimulates the expression of genes required for the entry into S-phase (DNA replication). 4. At the end of mitosis, RB is dephosphorylated, which renders it active.,The p53

16、protein is a nuclear phosphoprotein of 393 amino acids, which have three domains. N-terminus (1-80) transcriptional activation domain. Core section (102-290) which binds to DNA in a sequence specific manner. C-terminus (319-393) involved in the oligomerization of the protein.,Functions of p53 protei

17、n: The p53 protein can protect the integrity of the DNA. In the presence of DNA damage, the p53 protein can bring about a halt in the cell cycle at the G1/S transition, and promote DNA repair associated gene express. The p53 protein functions as a sequence-specific transcription activator, which is able to bind specifically to DNA elements and to activate the transcription of downstream genes. The p53 protein is involved in initiation of programmed cell death (apoptosis).,When p53 is mutant (loss-of-function), this regulatory pathway does not work. Mutant P53 encode oncopro