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Cancer Cell Division & Genes
- 3. Cancer…
- 4. Licentious division - prostate cancer cells durin Cancer not a single disease; heterogeneous group of disorders characterized by the presence of cells that do not respond to the normal controls on division.
- 5. Normal cells
- 6. Cancer cells
- 7. Normal cells grow in monolayer Cancer cells grow in clumps (foci) COURTESY OF G. STEVEN MARTIN.)
- 8. Angiogenesis
- 9. Metastasis
- 10. Why a greater number of cells do not give rise to cancerous tumors ….???
- 11. > malignant transformation requires more than a single genetic alteration(hits).
- 12. How is a normal cell transformed into a cancerous cell?
- 13. Rather than lacking function, cancer cells reproduce at a rate far beyond the normally tightly regulated boundaries of the cell cycle. occur due to an alteration of a normal biological process — cell division.
- 16. Induction of malignant transformation with chemical or physical carcinogens appears to involve multiple steps and at least two distinct phases: initiation and promotion.
- 17. The signals that regulate cell division fall into two basic types: molecules that stimulate cell division and those that inhibit it.
- 18. Genes that have been implicated in carcinogenesis are divided into two broad categories: Tumor-suppressor genes and Oncogenes.
- 19. Tumor-suppressor genes Encode proteins that restrain cell growth and prevent cells from becoming malignant. Act recessively since both copies must be deleted or mutated before their protective function is lost.
- 20. Oncogenes > Encode proteins that promote the loss of growth control and malignancy. Oncogenes arise from Proto-oncogenes—genes that encode proteins having a role in a cell’s normal activities. Mutations that alter either the protein or its expression cause the proto-oncogene to act abnormally and promote the formation of a tumor.
- 22. MESSAGE The proteins that oncogenes encode are activated in tumor cells, whereas the proteins that tumor suppressor genes encode are inactivated.
- 24. Five broad classes of proteins are generally recognized as being encoded by tumor- suppressor genes Intracellular proteins that regulate or inhibit progression through a specific stage of the cell cycle (e.g., p16 and Rb) Receptors or signal transducers for secreted hormones or developmental signals that inhibit cell proliferation (e.g., TGF)
- 25. Checkpoint-control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal (e.g., p53) • Proteins that promote apoptosis • Enzymes that participate in DNA repair
- 27. TP53 : the guardian of genome… The product is a protein of 53 kilodaltons (hence the name). >The p53 protein prevents a cell from completing the cell cycle if its DNA is damaged or the cell has suffered other types of damage.
- 29. Loss-of-Function Mutations in Tumor-Suppressor Genes Are Oncogenic • deletions or point mutations • methylation of cytosine residues in the promoter or other control elements.
- 30. Loss of Heterozygosity Subsequent loss or inactivation of the normal allele in a somatic cell, referred to as loss of heterozygosity (LOH), is a prerequisite for cancer to develop.
- 31. Tumor suppressor gene in cancer cells
- 32. [Micrographs by E. R. Fearon and K. Cho. From W. K. Cavanee and R. L. White, Scientific American, March 1995, pp. 78–79.]
- 33. Oncogenes
- 35. Proteins encoded by proto-oncogenes
- 36. Conversion of proto-oncogenes into oncogenes
- 37. Gain-of-Function Mutations Convert Proto-oncogenes into Oncogenes • Point mutation (i.e., change in a single base pair) in a proto-oncogene that results in a constitutively active protein product • Chromosomal translocation that brings a growth regulatory gene under the control of a different promoter that causes inappropriate expression of the gene Five broad classes of proteins are generally recognized as being encoded by tumor- suppressor genes
- 38. • Amplification (i.e., abnormal DNA replication) of a DNA segment including a proto-oncogene, so that numerous copies exist, leading to overproduction of the encoded protein
- 40. POINT MUTATION OF AN INTRACELLULAR SIGNAL TRANSDUCER
- 42. [Adapted from B. Vogelstein and K. W. Kinzler, 1993, Trends Gene Model of sequential genetic alterations leading to metastatic colon cancer.
- 43. Although oncogenes or mutated tumor-suppressor genes or both are required to produce cancer, mutations in DNA repair genes can increase the likelihood of acquiring mutations in these genes.
- 44. Cancer is currently treated by surgery, chemotherapy, and radiation. Several other strategies are being tested; these include # immunotherapy, # inhibition of proteins encoded by oncogenes, # inhibition of angiogenesis.
- 46. REFERENCES 1. Molecular Cell Biology- Lodish, Baltimore et al, Freeman and Co. 2. Cell and Molecular Biology- Concepts and Experiments- Karp (2012) 5th edn., John Wiley and sons 3. www.youtube.com 4.http://www.biooncology.com/
- 47. RAHUL E M BPS051416 SI PLANT SCIENCE CUK
Hinweis der Redaktion
- Cancers figure among the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases and 8.2 million cancer related deaths. Common cancers include…lung…, The number of new cases is expected to rise by about 70% over the next two decades.
- As a tumor grows in size, it stimulates the formation of new blood vessels, a process termed angiogenesis (Figure 16.22). Blood vessels are required to deliver nutrients and oxygen to the rapidly growing tumor cells and to remove their waste products. Blood vessels also provide the conduits for cancer cells to spread to other sites in the body.
- The cells of an advanced tumor can separate from the tumor and travel to distant sites in the body, where they may take up residence and develop into new tumors.
- Other diseases are caused by the reduction or increase in function Diabetis –insulin Aids ..
- Hereditery variety of DNA- and RNA-containing viruses Carcinogens Chemicals.toxins ionizing radiation pesticides,insecticides About 30% of cancer deaths are due to the 5 leading behavioural and dietary risks: high body mass index, low fruit and vegetable intake, lack of physical activity, tobacco use, alcohol use. all of these agents act by causing changes in the genome of the transformed cell.
- # Initiation involves changes in the genome but does not, in itself, lead to malignant transformation. # After initiation, promoters stimulate cell division and lead to malignant transformation.
- These control mechanisms are similar to the accelerator and brake of an automobile. In normal cells (but hopefully not your car), both accelerators and brakes are applied at the same time, causing cell division to proceed at the proper speed.
- Promote apoptosis…
- Oncogenes act dominantly; >that is, a single copy will cause the cell to express the altered phenotype. >Most tumors contain alterations in both tumor-suppressor genes and oncogenes. >As long as a cell retains at least one copy of all of its tumor-suppressor genes, it should be protected against the consequences of oncogene formation. > Conversely, the loss of a tumor-suppressor function should not be sufficient, by itself, to cause the cell to become malignant.
- 1. The tumor-suppressor gene most often implicated in human cancer is TP53, whose product (p53) may be able to suppress cancer formation by several different mechanisms It does this by binding to a transcription factor called E2F. This prevents E2F from binding to the promoters of such proto-oncogenes as c-myc and c-fos. >Transcription of c-myc and c-fos is needed for mitosis so blocking the transcription factor needed to turn on these genes prevents cell division.
- >If the damage is minor, p53 halts the cell cycle — hence cell division — until the damage is repaired or if the damage is major and cannot be repaired, p53 triggers the cell to commit suicide by apoptosis. These functions make p53 a key player in protecting us against cancer; that is, an important tumor suppressor gene. More than half of all human cancers do, in fact, harbor p53 mutations and have no functioning p53 protein. Mice have been cured of cancer by treating them with a peptide that turns on production of the p53 protein in the tumor cells.
- In many cancers, tumor-suppressor genes have deletions or point mutations that prevent production of any protein or lead to production of a nonfunctional protein. Another mechanism for inactivating tumor-suppressor genes is methylation of cytosine residues in the promoter or other control elements. Such methylation is commonly found in nontranscribed regions of DNA.
- we can inherit a propensity to cancer by receiving a damaged allele of a tumor suppressor gene from one of our parents; that is, we are heterozygous for the mutation. That in itself will not cause cancer, since the remaining normal allele prevents aberrant growth; the cancer is recessive.
- The ras oncogene A single base-pair substitution that converts glycine into valine at amino acid number 12 of the Ras protein, for example, creates the oncoprotein found in human bladder cancer (Figure 17-16a). Recall that the normal Ras protein is a G-protein subunit that takes part in signal transduction. It normally functions by cycling between the active GTP-bound state and the inactive GDP-bound state (see Figure 17-12). The missense mutation in the ras oncogene produces an oncoprotein that always binds GTP (Figure 17-16b), even in the absence of normal signals. Thus, the Ras oncoprotein continuously propagates a signal that promotes cell proliferation.
- Gene ERBB2, a known proto-oncogene, is located at the long arm of human chromosome 17 (17q12. Human epidermal growth factor receptor (HER) pathways play a critical role in cancer biology . Dysregulation of HER-mediated signaling pathways results in the growth and spread of cancer cells.1 The HER family consists of 4 structurally related receptors: HER1 (EGFR), HER2, HER3, and HER4.1,2 HER family receptors are activated by ligand-induced dimerization, or receptor pairing.3 Dimerization is a critical step in HER family-mediated signaling, and HER receptors are able to homodimerize or heterodimerize with other HER family members, allowing for multiple receptor combinations.1,4 The formation of dimers leads to activation of the intrinsic tyrosine kinase domain and subsequent phosphorylation on specific tyrosine residues, which serve as docking sites for a variety of molecules. Recruitment of these molecules leads to the activation of different downstream signaling cascades, including the MAPK proliferation pathway and/or the PI3K/Akt prosurvival pathway.1,4-7 Inappropriate signaling may occur as a result of receptor overexpression or dysregulation of receptor activation, which may lead to8-10: Increased/uncontrolled cell proliferation Decreased apoptosis (programmed cell death) Enhanced cancer cell motility Angiogenesis
- Having mutated DNA repair genes is analogous to having a lousy car mechanic who does not make the necessary repairs to a broken accelerator or brake. >The genome of patients with the most common hereditary form of colon cancer, called hereditary nonpolyposis colon cancer (HNPCC), contains microsatellite sequences of abnormal nucleotide number.
- To date, the greatest success has come with the development of an inhibitor of Abl kinase in patients with chronic myelogenous leukemia. A second success story has been the development of humanized antibodies that bind to a protein on the surface of malignant B cells in cases of non-Hodgkin’s lymphoma. Antiangiogenic strategies attempt to prevent a solid tumor from inducing the formation of new blood vessels that are required to supply the tumor cells with nutrients and other materials. A number of agents have been identified that block angiogenesis in mice and have had limited success in clinical trials.