วัตถุประสงค์

1. 8. ยีนยับยั้งการเกิดเนื้องอก (Tumor Suppressor Genes) วัตถุประสงค์ • สามารถบอกบทบาทของ tumor suppressor genes ใน cell proliferation,cell death, DNA repair และ genetic stability ได้ • สามารถยกตัวอย่าง และอธิบายกลไกในการยับยั้งมะเร็งของ tumor suppressor genes ได้ เนื้อหา 8.1 Roles in cell proliferation and cell death 8.2 Roles in DNA repair and genetic stability

2. 8. Tumor Suppressor Genes • Tumor suppressor genesare genes whose loss or inactivation can contribute to cancer development. • Loss-of-function mutations of tumor suppressor genes can lead to cancer. 8.1 Roles in cell proliferation and cell death • Many tumor suppressor genes function to inhibit cell proliferation or promote cell death. • The loss of such functions would cause increased cell proliferation or decreased cell death.

3. 8.1.1 Cell fusion experiments provided the first evidence for the existence of tumor suppressor genes • In the late 1960s, hybrid cell experiments provided the earliest evidence that normal cells contain genes that can suppress tumor growth and reestablish normal controls on cell proliferation. Induced by inactivated Sendai virus • Reversion to malignant behavior is associated with the loss of certain chromosomes. ---> loss of tumor suppressor genes

4. 8.1.2 Study of inherited chromosomal defects and loss of heterozygosity have led to the identification of several dozen tumor suppressor genes. • Inherited chromosomal defect of RB: deleted segment in chromosome 13.

5. Loss of Heterozygosity Mitotic nondisjunction Mitotic recombination Gene conversion

6. 8.1.3 The RB tumor suppressor gene produces a protein that restrains passage through the restriction point. • RB = the first tumor suppressor gene that was isolated and characterized. • Rb protein restrains cell proliferation in the absence of growth factors.

7. Cancers triggered by a loss of Rb function can arise in two fundamentally different ways: 1) through mutations that delete or disrupt both copies of the RB gene. 2) through the action of viral oncoproteins that bind to and inactivate the Rb protein (e.g. E7 oncoprotein from HPV) • Since the discovery of the RB gene in the mid-1980s, dozens of additional tumor suppressor genes have been identified.

8. 8.1.4 The p53 tumor suppressor gene produces a protein that prevents cells with damaged DNA from proliferating • p53 = guardian of the genome • ATM kinase is produced by the ATM tumor suppressor gene : ATM = Ataxia Telangiectasia Mutated • Ataxia Telangiectasia ---> ~40% risk of developing cancers (mostly lymphomas, leukemias) • Mdm2 = ubiquitin ligase • Puma = p53 upregurated modulator of apoptosis

9. Ubiquitin plays a role in targeting proteins for degradation.

10. p53 is the most commonly mutated gene in human cancers. • Li-Fraumeni syndrome inherit a mutant p53 gene. ---> high risk of developing cancer • However, most p53 mutations are not inherited. • In some cases, mutation of one copy of the p53 gene may be sufficient to cause the p53 protein to be inactivated. ---> “dominant negative mutation” • The E6 oncoprotein from HPV binds to and targets p53 for destrution.

11. Comparison of Recessive and Dominant Negative p53 Mutations.

12. 8.1.5 The APC tumor suppressor gene codes for a protein that inhibits the Wnt signaling pathway. • Associated with “familial adenomatus polyposis”. ---> ~100% risk of developing colon cancer ( age of 60) ---> < 1%of all colon cancer • 2/3 of all colon cancers involve APC mutations. • APC gene codes for a protein involved in the Wnt pathway. • -catenin is the central component of the Wnt pathway. ---> activates cell proliferation during embryonic development. • Axin-APC-GSK3 destruction complex phosphorylates -catenin ---> -catenin is targeted by ubiquitin for degradation • GSK3 = glycogen synthase kinase 3

14. 8.1.6 The PTEN tumor suppressor gene codes for a protein that inhibits the PI3K-Akt signaling pathway. 50% of prostate cancers and glioblastomas ----> PTEN mutations PIP2 = Phosphatidylinositol-4,5-bisphosphate PIP3 = Phosphatidylinositol-3,4,5-trisphosphate Phosphatidylinositol 3-kinase = PI 3-kinase or PI3K

15. 8.1.7 Some tumor suppressor genes codes for components of the TGF-Smad signaling pathway • Transforming Growth Factor  (TGF ) may either stimulate or inhibit cell proliferation, depending on the cell type and context. • TGF  inhibits cell proliferation through the TGF -Smad pathway. Cdk inhibitors

16. Loss-of-function mutations in the TGF  receptor are common in colon and stomach cancers. • Loss-of-function mutations in Smad proteins are observed in a variety of cancers, including 50% of all pancreatic cancers and ~30% of colon cancers. 8.1.8 One genes produces two tumor suppressor proteins: p16 and ARF ----> P16 and ARF exhibit no sequence similarity. (INK4a) ARF = Alternative Reading Frame ----> 15%-30% of all cancers originating in the breast, lung, pancreas, and bladder.

17. 8.2 Roles in DNA repair and genetic stability • Tumor suppressor genes involved in DNA maintenance and repair are considered to be “caretakers” that preserve the integrity of the genome. 8.2.1 Genes involved in excision and mismatch repair help prevent the accumulation of localized DNA errors

18. 8.2.2 Proteins produced by the BRCA1 and BRCA2 genes assist in the repair of double-strand DNA breaks • Loss-of function of one of BRCA genes; - risk of 40-80 % for breast cancer, 15-65 % for ovarian cancer. - cells exhibit broken chromosomes, chromosomal translocations. Repairing double-strand DNA breaks by Homologous Recombination.

19. 8.2.3 Mutation in genes that influence mitotic spindle behavior can lead to chromosomal instabilities Distributing Chromosomes During Mitosis

20. The “wait” signal that inhibits the anaphase-promoting complex are members of the Mad and Bub families. • Genes coding for some of the Mad or Bub proteins behave as tumor suppressor gene. • The anaphase-promoting complex initiates chromosome movement by activating separase, an enzyme that breaks down proteins called cohesins that hold the duplicated chromosomes together.

21. Theloss of spindle checkpoint creates aneuploid cells.