Cell Cycle and Cancer Cell Cycle According to
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Cell Cycle and Cancer Cell Cycle According to Lewin (2002) ‘The intermediate time between two consecutive cell divisions is known as cell cycle”. Cell cycle is a sequence of events involving the periodic replication of DNA and the segregation of this replicated DNA with cellular constituents to daughter cells. i. e. , the sequence of events which occur between one cell division and the next. Uncontrolled, growing mass of cells, that is capable of invading neighbouring tissues and spreading via body fluids, especially the blood stream, to other parts of the body is known as cancer.
Adult Human Cell Replicating human cells complete the full cell cycle in about 24 hours. Mitosis takes about 30 minutes, G 1 9 hours, the S phase 10 hours and G 2 4. 5 hours. Yeast cell takes only 90 minutes to complete one cycle.
Embryonic Cell The functional anatomy of a typical embryonic cell cycle is slightly different. In the early embryonic cell cycle, no noticeable growth occurs. As a result, each of the two daughter cells of each division is half the size of the parent cell. The cycle time is extra ordinarily short and S phase and M phase alternate without any intervening G 1 and G 2 phases. In few some cases the embryonic cells divide very fast and cell cycle takes 8 -60 minutes. S phase takes half of the time and other half is the M phase. G 1 and G 2 phases are almost absent (Alberts et al. , 1994)
Phases of Cell Cycle Mitotic phase (M Phase) Prophase Condensation of chromosomes take place. Nucleolus disappears , nuclear membrane disintegrates. Metaphase Sister chromatids produced by DNA replication during S phase remain attached at the centromere and become aligned in the centre of the cell. Anaphase During anaphase the sister chromatid separates and moves to opposite poles of the mitotic apparatus (spindle) segregating one of the two sister chromatids to each daughter cell. Telophase The nuclear envelop reforms around the segregated chromosome, decondensation takes place. Cytokinesis The physical division of the cytoplasm called cytokinesis then gives rise to two daughter cells.
Mitosis Cell Division Prophase Metaphase Anaphase Telophase and Cytokinesis
Interphase • The Interphase can be divided into following 3 phases. • Gap 1 or G 1 Phase : Following mitosis the cycling cell enters the G 1 phase. Growth and increase in cell mass that occurs following cell division. Metabolic activities are associated with cell growth and preparation for DNA replication. • Synthesis phase or S Phase : Cell replicates its DNA at this phase and the amount become double. The material of each and every chromosome is replicated. The number of chromosomes does not vary. • Gap 2 or G 2 Phase : After completion of DNA replication cell enters into another phase called G 2 phase. It is the post DNA replication phase. Preparation for mitotic cell division takes place at this phase.
G 0 phase • • Most of the post mitotic cells in vertebrates exist the cycle in G 1 and enter the G 0 phase, a quiescent or resting phase and the cells are called resting cells. The cells can exit cell cycle after mitosis and remain for days, weeks or in some cases even the life time of the organism without proliferating further. e. g. nerve cells, cells of eye lens. Neurons reside in this state, not because of limited nutrient supply, but as a part of their internal genetic programming. From G 0 phase cells re-enter the cycle directly at S phase when get the right signal (liver cells). G 0 states can be categorized as either reversible (quiescent) or irreversible (senescent and differentiated). Quiescent cells are identified by low RNA content and absence of nutrients or growth factors cause cells to enter a resting state. It is a reversible process. Senescence is distinct from quiescence because senescence is an irreversible state that cells enter in response to DNA damage or degradation that would make a cell's progeny nonviable. Such DNA damage can occur from telomere shortening over many cell divisions. While senescent cells can no longer replicate, they remain able to perform many normal cellular functions. Senescence is often a biochemical alternative to the self-destruction of such a damaged cell by apoptosis. Differentiated cells are stem cells that have progressed through a differentiation program to reach a mature – terminally differentiated – state. Differentiated cells continue to stay in G 0 and perform their main functions indefinitely. Many different types of tissue stem cells exist, including muscle stem cells (Mu. SCs), neural stem cells (NSCs), intestinal stem cells(ISCs), and many others. These stem cells are activated in response to any injury or damage.
Control System and Check Points of Cell Cycle Cell division is well controlled in normal condition. For correct control of the cell there exists a central cell cycle control system which regulates the orderly progress of events during the cell cycle. Before the progression of cell to the next phase of the cycle, the cell needs to complete the previous phase properly. Premature entrance of cell to the next phase results in a serious consequences which even leads to cancer. To overcome the occurrence of mistakes in cell cycle events, the cell progress through the cycle is monitored at three key check points which act like a break in a cycle and prevent the cell from any accident.
G 1 Check Point: G 1 Phase<<<<-G 1 Check Point ->>>> S Phase Restriction point in mammalian cells and Start point in yeast. • It is the point at which the cell becomes committed to enter the cell cycle. • Cells have to check following conditions before entering the S phase. • The cytoplasm nucleus(C/N)ratio. • Environment should be favourable. • Cells must have enough energy reserve. • Anaphase Promoting Complex (APC) must be inactive. • DNA damage has to be repaired. After the examination of the above events the cell can enter the S phase. If detected any defect the cell can halt the cycle and attempt to recover the problem. If recovery is not possible the cell can enter the G 0 phase, wait for further signal when the condition improve.
G 2 Check Point : G 2 phase<<<-G 2 Checkpoint->>> Mitotic phase Prevents the entry of cell into the mitotic phase if following conditions are not met. • DNA synthesis and repair to be completed. • All the chromosomes have been replicated and the replicated DNA must not be damaged. • Environment must be favourable. • Sufficient development must have occurred. • If any problem has been detected within DNA the cycle will halt and the cell will attempt to complete DNA replication or repair the damaged DNA. If it is not possible for the cell to repair the damage, the cell may undergo apoptosis. This self destruction mechanism ensures that damaged DNA is not passed on the daughter cells and is important in preventing cancer.
Metaphase (M) Check Point: Metaphase<<< M Check Point>>>Anaphase Mitotic cdk complexes synthesized during the S phase and G 2 phase but their activities are checked until DNA synthesis in completed. The check point detect whether the following conditions have been fulfilled or not. • Whether DNA has been replicated only once. Whether all the sister chromatids are correctly attached to the spindle microtubules. • APC (Anaphase Promoting Complex) is no Longer inhibited. • If the answers to the above questions are in the affirmative, the cell ensures to divide.
Molecular Control of Cell Cycle The cell cycle is regulated by some enzymes known as protein kinases. These kinases are regulated by cyclins which increase and decrease in phase with cell cycle. The kinase enzymes are known as cyclin dependent kinases (Cdks) are the key components of the regulatory events that occur at check points. Each Cdk catalytic subunit can associate with different cyclins and the associated cyclin determines which proteins are to be phosphorylated by the cdk cyclin complex. The passage through the cyclin is controlled by G 1 cyclin dependent kinase complex (G 1 Cdkc), S phase cyclin dependent kinase complex (S-phase Cdkc) and Mitotic cyclin dependent kinase complex (mitotic Cdkc). Cyclin dependent kinase complex G 1 Cdk complex expressed first in the cell cycle which prepares the cell for S phase and is involved with following functions : • Activates transcription of S-phase Cdkc components. • Phosphorylates S-phase Cdkc inhibitor. • Induce the degradation of the S-phase inhibitor releasing the activity of the S-phase Cdk complexes. • Inactivates APC. S-phase Cdk complexes stimulate the entry of cell to the S-phase. It perform the following activities within the cell cycle : • Phosphorylate regulatory sites in the proteins that form DNA pre-replication complexes. • Initiate DNA replication. • Prevents re-assembly of pre-replication complexes so that each chromosome is replicated only once during passage through the cell cycle and the proper chromosome number must be maintained.
Maturation Promoting Factor (MPF) Mitotic cyclin (M-cyclin) + Mitotic cyclin-dependent kinase (M-Cdk , P 34 and P 45 ) • • • Entry of cell into mitosis is regulated by Maturation Promoting Factor (MPF). MPF is also known as Mitosis Promoting Factor. MPF is composed of mitotic cyclin (M-cyclin) and mitotic cyclin-dependent kinase (M-Cdk). The mitotic Cdk consists of two subunits P 34 and P 45 P 34 is a kinase catalytic subunit which phosphorylates the target protein and becomes active at the beginning of the M-phase. P 45 is a regulatory subunit known as cyclin which has kinase activity with appropriate substrate. Mitotic cyclin synthesized and accumulated during the S-phase and G 2 phase and unites with Cdk molecules to form M-phase Promoting Factor (MPF). It is inactive at the preliminary stage, but becomes active after the synthesis of DNA become completed. Active MPF promotes entrance of cell to mitosis and once activated induce the following activities within the cell. Chromosome condensation. Break down of nuclear envelope. Assembly of mitotic spindle apparatus. Alignment of condensed chromosomes at the metaphase plate. Activation of Anaphase Promoting Complex (APC). At the junction of metaphase and anaphase, MPF suddenly become inactive MPF helps switch itself off by initiating a process that leads to the destruction of its cyclin by a protein breakdown mechanism. This triggers the cell to exit from mitosis.
Anaphase Promoting Complex (APC) APC showing two actions • Anaphase promoting complex, also known as cyclosomes or APC/C is a multiprotein complex, directs the proteolysis of anaphase inhibitors and trigger the transition from metaphase to anaphase by triggering specific proteins for degradation. • The three major targets for degradation by APC/C are securin and S and M cyclin. Inactivation of protein complex (cohesin) that connect sister chromatids at metaphase takes place by : • ubiquitination of securin by the APC/C and releases separase (a protease) which degrade cohesin.
Anaphase Promoting Complex (APC) • Separase triggers the cleavage of cohesin which binds sister chromatids together at metaphase. Sister chromatids become free and segregate to opposite poles. • The APC/C also targets the mitotic cyclins for degradation. • M-Cdk (Mitotic Cyclin-dependent kinase) complexes become inactivate. • Exit from mitosis takes place and drives the cycle forward by • the formation of nuclear envelope • division of cytoplasm • decondensation of chromosomes • formation of two daughter cells. • APC/C also plays a major role in maintenance of chromatin metabolism in G 1 and G 0 stage.
CANCER Uncontrolled, growing mass of cells, that is capable of invading neighbouring tissues and spreading via body fluids, especially the blood stream, to other parts of the body is known as cancer. The term cancer means ‘crab’ in Latin was coined by Hippocrates in the fifth century B. C. to describe diseases in which tissue grow and spread throughout the body. It is an abnormal type of tissue growth in which some cells divide and accumulate in an uncontrolled and relatively in autonomous way, leading to progressive increase in number of dividing cells. This mass of growing tissue is known as tumour (or neoplasm). Tumours are classified as either benign or malignant on the basis of their growth pattern. Benign tumours grow in a confined local area and are generally not dangerous Malignant tumours are capable of invading surrounding tissues, entering the blood stream and spreading to distant part of the body (metastasis). The term cancer refers to any malignant tumour.
Differences between Benign tumour and Malignant tumour Benign tumour • • • Nucleolus remains same as normal cell. No changes take place in cytoplasm. The cells are of uniform shape. Slow growth. Do not metastasize to other part of the body. May not require treatment if not health threatening. Malignant tumour • • • Hyperchromatic DNA, the nucleolus enlarges. Size of cytoplasm diminishes in relation to nucleus. Cells are of various shapes. Fast growth. Can spread through blood stream or lymphatic system i. e. metastasize. May require treatment including surgery, radiation chemotherapy and immunotherapy medications .
Depending on the cell type involved, cancer can be grouped into several different categories. • Carcinomas : Cancer of epithelial cells. 90% of cancer arise from epithelial cells that cover external and internal body surfaces. e. g. Lung, breast and colon cancer. • Sarcomas : Develop from supporting tissues such as bone, cartilage, fat and muscle. Mesodermal in origin. • Lymphomas and Leukaemias : Arise from cells of blood and lymphatic origin. Approximately 8% of human malignancies arise from the cells of the immune system (lymphoma) and from blood forming cells (leukemia). Mixed Malignant Tumour: Arising from both mesodermal and ectodermal tissues. • • The above mentioned cancers occur frequently but there are more than a million cases of cancer are diagnosed annually. The most common cancer are those of the prostate (1. 28 million), breast (2. 09 million), lung (2. 09 million), skin (1. 04 million), stomach (1. 03 million), and colorectal. About 30% of all cancer death is due to lung cancer. • In the ancient world most deaths were due to infectious diseases, such as pneumonia, tuberculosis etc. and life expectancy was less than 50 years. At that time cancer was a rare disease and only a small percentage of people died of cancer. But in the recent years cancer is a leading cause of death worldwide, accounting for an estimated 9. 6 million
Characteristics of cancer Cells • All most all types of cells can become neoplastic or cancerous. Cancerous cells generally retains the structural and functional characteristics of the normal cell type from which it derives. Thus cancerous cells of the thyroid gland continue to secret thyroxin. Neoplastic cells differ from normal cells in following aspects: • • Immortalization: Normal human cells generally die after 50 generations. Transformed cell culture can grow indefinitely. Loss of contact inhibition: When two normal cells come in contact with one another, both stop moving and then move in another direction and stop growing. Neoplastic cell continue to grow even after contact until overcrowding kill them. Cancer cell loss the property of recognition by plasma membrane. Reduced cellular adhesion: Adhesiveness shows considerable specificity. Each cell type tends to stick to its own cell type and not to other cell type. Cancerous cells do not show this property. This explains why malignant cells can invade several normal organs by metastasis. Invasiveness: It is the ability of cancer cell to invade other tissues. Loss of cell adhesion capacity allows malignant tumour cells to dissociate from the primary tumour mass and enable the cells to invade the surrounding. Molecular changes in cell membrane components : Disorganization of cytoskeleton: Increased sugar transport, increased rate of glycolysis. Increased secretion of proteolytic enzymes.
Characteristics of Cancer cells
Cancer Genetics • Genes that are involved in cell division can be divided mainly into two types. • Proliferation genes : Helps to corss the check points of the cell and cell growth takes place. When proliferation gene mutate, the activity of the gene increases and the division of cell increases in uncontrolled way. The mutated proliferation gene is known as oncogene and its normal allele is known as protooncogene. • Antiproliferation genes: Acts as break and inhibit cell division. Cell cycle function properly by the coordination of these two types of genes. When antiproliferation gene mutate, it affects and damage the check points which acts as the break of the cell cycle. The normal antiproliferation gene is known as tumour suppressor gene. • When both the alleles of the tumour suppressor genes mutate in a normal diploid cell, uncontrolled cell growth takes place, i. e. , the effect of the gene is recessive. • When one allele of protooncogene mutate, cell cycle becomes uncontrolled i. e. , the effect of the gene is dominant. • Many different genes control cell growth in a systematic way. The formation of tumours result from uncontrolled cell division and cell growth. When these genes have an error i. e. , they altered or mutate they may not work properly and damage the check points. Accumulation of mutations in different genes occurring in a specific group of cells over time required to cause malignancy. The different types of genes that when mutated can lead to the development of cancer.
oncogene • An oncogene is a mutated form of a normal cellular gene–called a protooncogene which is responsible for creating cancer. It is defined as a gene that encodes a protein that is capable of transforming cells in culture or inducing cancer in animals. • Peyton Rous in 1911 first discovered retrovirus from the sarcoma cancer of fowl. The first confirmed oncogene was discovered in 1970 by Peter Vogh and Steven Martin. They proved this substance as a genetic substance and was named as src oncogene which comes from sarcoma (a tumour of connective tissue). src was first discovered as an oncogene from tumour in a chicken. The tumour filtrate was able to induce cancer when injected into other chicken. The transforming agent in the filtrate was shown to be a virus, called Rous Sarcoma Virus (RSV). Rous was awarded Noble prize for his pioneering work in 1966. RSV is a retrovirus whose RNA genome is reverse transcribed into DNA which is incorporated into host cell genome. • Oncogenes are genes involved either transforming cells in culture or in inducing cancer in animals. Oncogenes were initially identified as genes carried by viruses and the viral part of oncogenes is know as v-onc. The viral oncogenes have cellular counterparts that are involved in normal cell functions. Some gene sequence have been identified in the host cells and the gene is expresed as c-onc i. e. cellular oncogene. For a particular oncogene, the onc is replaced by the three letters sequence of the related viral oncogene, e. g. v-src and c-src.
Protooncogene • A group of scientists Harold Varmus, Michel Bishop and colleagues in 1976 proved that oncogene of retrovirus originates from the gene of normal cells, so they have named the host gene i. e. , the cellular oncogene (c-onc) as protooncogene. • The protooncogene is a normal gene. There are many protooncogenes and they are responsible for various functions for maintaining healthy tissues and organs in our body. Functions of Protooncogenes In normal condition protooncogenes are involved with following functions : • Regulate cell division and differentiation. • Promote cell growth and proliferation. • Direct the synthesis of proteins that regulate signal transduction pathway of the cell. • Prevent apoptosis. • In normal condition protoocogenes remain in an inactive state. But they activated in many ways like mutation and sometimes by integration of retroviral genome and ultimately transforms into oncogene. Malfunctioning of protooncogene leads to uncontrolled cell growth and convert the protooncogene to a cancer promoting oncogene and induce tumour formation. The mutation that convert protooncogenes to oncogenic alleles are known as activating mutations. Most but not all oncogenes in the body arise from protooncogenes. The human oncogenes are very similar to viral oncogenes.
Transformation of Cellular Protooncogenes to Oncogenes • • The protooncogene is a normal gene. In normal cells the function and expression of protooncogene is well controlled so that cell growth and division occur according to the necessity of the particular cell type. But when protooncogenes are changed into oncogenes the well controlling power become lost and unregulated cell proliferation takes place. Journey from a normal cell to become a cancer cell i. e. way to become an oncogene is a step by step process through mutation that occur in three different types of genes. One is growth regulatory gene, 2 nd is apoptotic gene and the 3 rd one is tumour suppressor gene. The types of changes that occur due to mutation in these genes are discussed below. Translocation: This mutation is very common in human tumour cells and some are specific for certain tumour types. e. g. Chronic myelogenous leukemia (CML) and Philadelphia chromosome produced by a reciprocal translocation involving chromosomes 9 and 22. Burkitt’s lymphoma resulting from a reciprocal translocation involving chromosome 8 and 14. Gene amplification: Some tumours have multiple copies of protooncogenes. Extra copies of the protooncogene in the cell result in an increased amount of gene product which induces uncontrolled cell division. e. g. multiple copies of ras are found in mouse adrenocortical tumours. Point mutations : Base pair substitution in promoter, regulator, enhancer in region (within a control element) or in the coding regions (within the gene) can change a protooncogene to an oncogene causing an increasing or altering the activity or expression of the protooncogene. e. g. ras mutation is a typical point mutation. The protooncogene encode protein (G protein) has a role in cell signaling. When ras genes are mutated, cells grow uncontrollably and evade death signals. A single point mutation generally in codon 12, 13 or 61, results in a mutant protein that can transform normal cells into malignant cells. Deletions : Deletions in the coding or controlling sequences of protooncogenes found frequently. It changes the growth stimulatory protein activity causing unprogrammed activation of some cell proliferation gene. e. g. myc oncogene can arise from its protooncogene by deletion. The normal protooncogene consists of three exons and two introns. In myc oncogenes, the first exon and most of the first intron are deleted. Deletions brought a change in the activity of the remaining Myc protein chain. Thus oncogene is modified form of protooncogene that increases the malignancy of a tumour cell.
Comparison of cellular Oncogene and viral Oncogene Cellular oncogene (c-onc) • Cellular oncogenes are present in normal vertebrate genome in inactive form. • The genes have multiple exons separated by introns. • The chicken cellular src protooncogene contains 12 exons and 11 introns. • c-Src protein is 533 amino acid long. • Regulates cell division and cell proliferation. . Viral oncogene (v-onc) • These genes produce tumour immediately after entering the host cell. • Have single exon and no introns. • In Rous sarcoma virus, v-src gene has single uninterrupted coding sequence. • v-Src protein is 526 amino acid long. • These genes are transduced to normal host cell and induced oncogenesis.
umour Suppressor Gene • . Any gene whose encoded protein directly or indirectly inhibits progression through the cell cycle is known as tumour suppressor gene. The normal products of tumour suppressor genes have an inhibitory role in cell growth and division. When both the alleles of the tumour suppressor genes are inactivated due to mutation, the inhibitory activity is lost and uncontrolled cell proliferation takes place. This loss of function mutations that occur in tumour suppressor genes are recessive in nature. In order for a particular cell to become cancerous, both of the tumour suppressor genes must be mutated. This idea is known as “two-hit” hypothesis and was first proposed by geneticist Alfred Knudson in 1971. This hypothesis serves as a basis for researchers understanding of how mutations in tumour suppressor genes derive cancer. Two inactivating mutations functionally eliminate the tumour suppressor gene, stimulating cell proliferation. Inactivation of tumour suppressor genes are related to the development of various types of cancer. e. g. breast cancer, lung cancer and colon cancer. Thus tumour suppressor genes are opposite to protooncogenes. One gene check uncontrolled proliferation and the other promote proliferation. The former is called antiproliferation gene (tumour suppressor gene) and the latter is known as proliferation gene (protooncogene). The mutated proliferation gene is the oncogene.
Differences between Oncogene and Tumour suppressor genes Oncogene • Promotes cell proliferation and can transform a cell into a cancerous cell. • Acts as dominant to wild type i. e. , mutation in one of the two alleles cause cancer. Tumour Suppressor gene • Normally inhibit uncontrolled cell proliferation. Reduction in activity of these genes result in the development of cancer. • Acts in recessive condition. Mutation in both alleles are needed for the cell to loose their activity which ultimately develop cancer.
• The tumour suppressor gene p 53 located on the short arm of chromosome 17 is known as “Guardian of Genome” or “Molecular Police Man”. The gene p 53 is so named because it encodes a protein of molecular weight 53 KDa. • In normal condition p 53 gene synthesizes protein which function normally and prevent normal cell from being cancerous. But defective protein will form from mutated p 53 gene which will turn normal cell into cancerous cell. • • p 53 checks the cell cycle at G 1 check points and do not allow the cell to enter the S phase. If there is any damaged DNA, apoptosis of cell takes place. That is why p 53 gene is known as “Guardian of the Genome. ” • • p 53 gene may be involved in the development of 50 percent of human cancer such as breast, brain, lung, colon, liver, bladder and blood cancer. Several genetic changes found in these cancer are due to mutation in p 53 or absence of p 53 (Lewin, 1997). • P 53 gene influence the activities of the other genes. When one allele of the p 53 gene mutates, DNA repair and synthesis takes place in normal way. But when both the alleles mutate, DNA repairing and synthesis is not possible. Cell passes from G 1 to S phase and division becomes
The Retinoblastoma Tumour Suppressor Gene (RB Gene) • • The most common eye tumour in children. Birth to 4 year of age. The disease occurs both as Heritable trait Somatic mutation. The wild type gene is RB+ and it mutate to RB–. The effect of the gene is recessive i. e. retinoblastoma occurs when both copies of the RB gene are inactivated Hereditary Retinoblastoma : In heriditary retinoblastoma one mutant allele of RB is inherited and mutation in the other allele leads to the development of tumour and cancer. The second RB mutation is sometimes results in an identically mutated allele to the inherited one. The chromosomal region with the wild type RB allele is replaced by a duplicated copy of the homologous chromosome region that carries the mutant allele. Mitotic recombination, chromosomal non disjunction or gene conversion results in developing this type of mutation. This gives rise to cell that produces non functional RB protein. Thus loss of functional mutation in tumour suppressor gene (RB gene) are oncogenic. Somatic or Sporadic Retinoblastoma : In somatic retinoblastoma the inherited parental chromosomes are normal. Both the Rb alleles are to be deleted, mutate or lost by individual somatic events in a single retinal cell for development of tumour. Because of this reason somatic retinoblastoma is rare and develops late in life. Viral Retinoblastoma : Sometimes cells become infected with certain DNA tumour viruses. Viral proteins bind to RB blocking its ability to bind to members of the E 2 F family of transcription factors and allowing these factors to untime activation of genes for G 1–S transition and leads to viral induced uncontrolled cell division. In normal cells, phosphorylation and dephosphorylation of RB protein occurs at a definite time. But cells with two mutant RB alleles produce a shortened or unstable RB that does not bind to E 2 F. As a result genes for G 1–S transition become activate untimely leads to unprogrammed cell division.
Two hit hypothesis and Retinoblastoma Alfred Knudson describes the “two hit” mutation model for retinoblastoma in the year 1971. In somatic or sporadic retinoblastoma child starts with two wild type alleles (RB/RB). Both alleles must mutate to produce the disease (Rb/Rb). The probability of this occurring is low because both alleles have to mutate. So tumour will be in one eye and will develop late. In hereditary retinoblastoma child starts with heterozygous allele (Rb/RB). Only one mutation is require to produce the disease (Rb/Rb). This loss of heterozygosity is more probable and the tumour can be occur in both eyes and will develop early.
ras Gene ras is a family of gene that makes proteins involved in cell signaling pathways and control cell growth and cell death. The family of gene includes K-ras, H-ras and N-ras genes. The first two genes Kirsten sarcoma virus and Harvey sarcoma virus were originally discovered from rat sarcoma in the year 1960 by Jennifer Harvey (1964) and Werner Kirsten (Kirsten et al. (1970) respectively at the National Institute of Health (NIH) (Chang et al. , 1982). Hence the name rat sarcoma (Malumbres and Barbacid, 2003). The third ras gene N-ras was discovered by a group of researchers at the Institute of Cancer Research (Marshall et al. , 1982, Hall et al. , 1983) and Michael Wigler and cold spring Harbour Laboratory. In N-ras the N comes from its initial identification in human neuroblastoma cells. Function of ras gene Ras protein family members are the important component of the signal transduction pathway used by growth factors to initiate cell growth and differentiation. Cell activation with growth factors such as epidermal growth factor (EGF) induces Ras to move from an inactive GDP-bound state to an active GTP bound state. Thus Ras protein function as a binary molecule that is switch “on” in active state and switch “off” in an inactive state. After binding EGF, the EGF receptor tyrosine kinase (RTK) is activated. The active Ras is then transmit signal to mitogen activated protein (MAP) kinase. It then phosphorylates a number of transcription factors that induce the expression of cell cycle and differentiation. Mutations affecting the three isoforms of the ras family protooncogene are very common (20 -30%). The mutated form of oncogenes have the potential to cause normal cells to become cancerous. A point mutation in ras gene at 12 th, 13 th and 61 st position substituting any amino acid for glycin can convert normal protein into a constitutively active oncoprotein whose switch is always “on” and provides an excessive or uncontrolled growth promoting signal. This
Genetic Basis of Cancer Inheritance of the mutant allele in the germ cell alone can not form cancer. Somatic mutation and mitotic recombination also play important role in developing cancer. The genetic basis of cancer can be discussed into following three steps. Initiation : In the first step changes in the genetic material of a normal cell takes place. Normally protooncogene and tumour suppressor genes encode proteins that regulate cell cycle progression and suppress oncogenesis. Mutations in these two classes of genes play crucial role in cancer initiation. Promotion : The unnatural mutated cell divides continuously forming a clone of cells which congregate to form a tumour. Conversion of protooncogenes to oncogenes and mutated tumour suppressor genes collectively participate in the generation of tumour. Progression : Further mutation of genetic material of these abnormal cells result in the development of cancer. Usually oncogenes are dominant as they contain gain of function mutation while mutated tumour suppressor genes are recessive as they contain loss of function mutations. Mutation in one allele of protooncogene is enough to convert that gene into a true oncogene, while loss of function mutation have to occur in both alleles of a tumour suppressor gene to render the gene completely non functional. Loss of functional mutation in one allele render the other allele functional. The phenomenon is called dominant negative effect and is noted in many p 53 mutations. • • Is Cancer Hereditary ? Though mutation in DNA causes cancer, it is controversial whether it is completely hereditary or not. Many cancers run in the families and immediate relatives of patients where cancers often have an increased risk. BRCA 1 and BRCA 2 are examples of genetic mutation that give rise to increased risk of breast cancers. The patterns of familial clustering is more in some cancer like breast cancer, colon cancer and ovarian cancer but less in many other types of cancer like lung cancer, prostate cancer and oesophageal cancer. A person carrying the mutation in APC gene (the gene causing colon cancer) has 100% risk of developing colon cancer in late adult hood. But all theses require the interactions of groups of genes and various environmental factors common to the family like eating habits and food preferences. How much this increased risk is caused by environmental factors is difficult to detrmine. Thus most of the familial cancers are multifactorial and there are no demonstrable genetic markers or patterns. A small percentage of the cancers can be truly genetic with identifiable genetic markers.
Cancer – A Multistep Process In most of the cases cancer develops from accumulation of mutations in a number of genes. In order to develop a cancer six or seven independent mutations are needed over several decades of life. These mutations involve both activation of oncogenes and inactivation of tumour suppressor genes. Genes responsible for colon tumour lie in different chromosomes. Some are tumour promoter genes and some are tumour suppressors. A cascade series of several genes mutate to develop a colon cancer. Patients with familial adenomatous polyposis (FAP) develop hundreds to thousands of colon polyps usually starting in the teenage. All patients will develop cancer from the colon polyp by the age of 40. FAP patients inherit the loss of a tumour suppressor gene on chromosome 5. The gene is known as APC (adenomatous polyposis coli). In sporadic cases the same gene can be lost. Once both alleles of APC are lost in a colon cell, increased cell growth will result. Due to loss of APC the normal cells divide in an uncontrolled manner and adenoma class I develops (a benign). A second gene is K-ras. Due to its activities cell congregate to form tumour known as adenoma a benign tumour. After this when mutation occurs again chromosome 12 ras protooncogene converts into an oncogene. At this stage the cells proceed to a larger benign tumour known as adenoma class II.
Cancer – A Multistep Process In the next stage both the copies of the DCC gene (deleted in colon cancer), a tumour suppressor gene of chromosome 18 if lost by mutation, the primary adenoma is converted into a matured adenoma– the adenoma class III, the large benign polyps. Next by deletion of both copies of the chromosome 17 p 53 gene results in the conversion to a carcinoma (a cancer) and with the loss of other genes finally reaches at the metastatic stage. This multistep nature of cancer involves mutational events that activate oncogenes and inactivate tumour suppressor genes causing uncontrolled and unprogrammed growth and differentiation.
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