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Replication, P53 Gene, Histones, Cell Cycle, and Cancer

Cell Cycle and Histones. . ChromosomesNucleosomeContains a nucleosome core particle146 base pairs of supercoiled DNAAround a core of eight histone moleculesHistone coreTwo copies of H2A, H2B, H3 and H4OctamerH1 resides outside of coreLinker histoneBinds to linker DNAConnecting one nucleos

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Replication, P53 Gene, Histones, Cell Cycle, and Cancer

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    1. Replication, P53 Gene, Histones, Cell Cycle, and Cancer Robert F. Waters, Ph.D.

    2. Cell Cycle and Histones

    3. Chromosomes Nucleosome Contains a nucleosome core particle 146 base pairs of supercoiled DNA Around a core of eight histone molecules Histone core Two copies of H2A, H2B, H3 and H4 Octamer H1 resides outside of core Linker histone Binds to linker DNA Connecting one nucleosome core particle to next

    4. Histones Continued

    5. Replication

    13. (Scanned from journal) Fig. 1 Cell. 1995 Jun 16;81(6):825-8. Qualifying for the license to replicate. Su TT, Follette PJ, O'Farrell PH. (Scanned from journal) Fig. 1 Cell. 1995 Jun 16;81(6):825-8. Qualifying for the license to replicate. Su TT, Follette PJ, O'Farrell PH.

    17. Electron micrograph of replicating chromosomal DNA from cleavage nuclei of Drosophila. The eye forms are the newly replicated regions. Electron micrograph of replicating chromosomal DNA from cleavage nuclei of Drosophila. The eye forms are the newly replicated regions.

    18. Summary ORC complex assembles at multiple origins ORCs associate with Cdc6 & Cdt1 and are “licensed” MCM/helicase complex is loaded on to the origin Ordered assembly of additional complexes leads to a competent pre -Initiation complex In S-phase, cell cycle regulated kinases trigger replication After initiation the pre-IC complex is dismantled to prevent premature re-replication without cell cycle Replication occurs at two classes of origins (early & late) Origins in most eukaryotes are very poorly defined Novel tools are defining new ARS sites on a genome-wide level High conservation of function from Bacteria to humans -though mechanistic details may differ in each species

    19. DNA Damage & Repair

    22. Consider the human genome as a 3.5 gigabyte hard drive filled with information of which greater than 95% is rubbish, corrupted etc.Consider the human genome as a 3.5 gigabyte hard drive filled with information of which greater than 95% is rubbish, corrupted etc.

    27. Replication

    28. Replication

    29. Replication

    30. Replication

    31. Replication

    32. Replication

    33. Replication

    34. Replication

    35. Replication

    36. Replication

    43. P53 Gene

    44. P53 Gene THE p53 GENE is a tumor suppressor gene, i.e., its activity stops the formation of tumors. If a person inherits only one functional copy of the p53 gene from their parents, they are predisposed to cancer and usually develop several independent tumors in a variety of tissues in early adulthood. This condition is rare, and is known as Li-Fraumeni syndrome. However, mutations in p53 are found in most tumor types, and so contribute to the complex network of molecular events leading to tumor formation.   

    45. P53 Continued  The p53 gene has been mapped to chromosome 17. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus cells divide uncontrollably, and form tumors.

    46. Other Tumor Suppressors THE PANCREAS is responsible for producing the hormone insulin, along with other substances. It also plays a key role in the digestion of protein. There were an estimated 27,000 new cases of pancreatic cancer in the US in 1997, with 28,100 deaths from the disease. About 90% of human pancreatic carcinomas show a loss of part of chromosome 18. In 1996, a possible tumor suppressor gene, DPC4 (Smad4), was discovered from the section that is lost in pancreatic cancer, so may play a role in pancreatic cancer. There is a whole family of Smad proteins in vertebrates, all involved in signal transduction of transforming growth factor-beta (TGF-beta) related pathways.

    47. Hereditary Prostate Cancer THE SECOND LEADING cause of cancer death in American men, prostate cancer will be diagnosed in an estimated 184,500 American men in 1998 and will claim the lives of an estimated 39,200. Prostate cancer mortality rates are more than two times higher for African-American men than white men. The incidence of prostate cancer increases with age; more than 75% of all prostate cancers are diagnosed in men over age 65. Despite the high prevalence of prostate cancer, little is known about the genetic predisposition of some men to the disease. Numerous studies point to a family history being a major risk factor, which may be responsible for an estimated 5-10% of all prostate cancers.   

    48. Ras Oncogene Cancer occurs when the growth and differentiation of cells in a body tissue become uncontrolled and deranged. While no two cancers are genetically identical (even in the same tissue type), there are relatively few ways in which normal cell growth can go wrong. One of these is to make a gene that stimulates cell growth hyperactive; this altered gene is known as an 'oncogene'. Ras is one such oncogene product that is found on chromosome 11. It is found in normal cells, where it helps to relay signals by acting as a switch. When receptors on the cell surface are stimulated (by a hormone, for example), Ras is switched on and transduces signals that tell the cell to grow. If the cell-surface receptor is not stimulated, Ras is not activated and so the pathway that results in cell growth is not initiated. In about 30% of human cancers, Ras is mutated so that it is permanently switched on, telling the cell to grow regardless of whether receptors on the cell surface are activated or not. Usually, a single oncogene is not enough to turn a normal cell into a cancer cell, and many mutations in a number of different genes may be required to make a cell cancerous. To help unravel the intricate network of events that lead to cancer, mice are being used to model the human disease, which will further our understanding and help to identify possible targets for new drugs and therapies.

    49. Colorectal Cancer A TP53 polymorphism is associated with increased risk of colorectal cancer and with reduced levels of TP53 mRNA Federica Gemignani1,2,5, Victor Moreno3,5, Stefano Landi1,2,5, Norman Moullan1, Amélie Chabrier1, Sara Gutiérrez-Enríquez1, Janet Hall1, Elisabeth Guino3, Miguel Angel Peinado4, Gabriel Capella3 and Federico Canzian1 We undertook a case-control study to examine the possible associations of the TP53 variants Arg>Pro at codon 72 and p53PIN3, a 16 bp insertion/duplication in intron 3, with the risk of colorectal cancer (CRC). The p53PIN3 A2 allele (16 bp duplication) was associated with an increased risk (OR 1.55, 95% CI 1.10-2.18, P=0.012), of the same order of magnitude as that observed in previous studies for other types of cancer. The Pro72 allele was weakly associated with CRC (OR=1.34, 95% CI 0.98-1.84, P=0.066). The possible functional role of p53PIN3 was investigated by examining the TP53 mRNA transcripts in 15 lymphoblastoid cell lines with different genotypes. The possibility that the insertion/deletion could lead to alternatively spliced mRNAs was excluded. However, we found reduced levels of TP53 mRNA associated with the A2 allele. In conclusion, the epidemiological study suggests a role for p53PIN3 in tumorigenesis, supported by the in vitro characterization of this variant.

    50. Gene Therapy p53 tumor suppressor gene therapy for cancer. Roth JA, Swisher SG, Meyn RE. Department of Thoracic and Cardiovascular Surgery, University of Texas, M. D. Anderson Cancer Center, Houston, USA. Gene therapy has the potential to provide cancer treatments based on novel mechanisms of action with potentially low toxicities. This therapy may provide more effective control of locoregional recurrence in diseases like non-small-cell lung cancer (NSCLC) as well as systemic control of micrometastases. Despite current limitations, retroviral and adenoviral vectors can, in certain circumstances, provide an effective means of delivering therapeutic genes to tumor cells. Although multiple genes are involved in carcinogenesis, mutations of the p53 gene are the most frequent abnormality identified in human tumors. Preclinical studies both in vitro and in vivo have shown that restoring p53 function can induce apoptosis in cancer cells. High levels of p53 expression and DNA-damaging agents like cisplatin (Platinol) and ionizing radiation work synergistically to induce apoptosis in cancer cells. Phase I clinical trials now show that p53 gene replacement therapy using both retroviral and adenoviral vectors is feasible and safe. In addition, p53 gene replacement therapy induces tumor regression in patients with advanced NSCLC and in those with recurrent head and neck cancer. This article describes various gene therapy strategies under investigation, reviews preclinical data that provide a rationale for the gene replacement approach, and discusses the clinical trial data available to date.

    51. Example of Pattern Recognition Cancer

    53. Class Predictor The General approach Choosing a set of informative genes based on their correlation with the class distinction Each informative gene casts a weighted vote for one of the classes Summing up the votes to determine the winning class and the prediction strength

    54. Validation of Gene Voting

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