The Cell Cycle Gone Awry Cancer and Mitosis. Mutagens give rise to cancer cells. There are a wide variety of mutagens which cause changes to our DNA:

The Cell Cycle Gone AwryThe Cell Cycle Gone Awry

Cancer and MitosisCancer and Mitosis

•Mutagens give rise to cancer cells.•There are a wide variety of mutagens which cause changes to our DNA:•Chemicals•UV radiation•Ionizing radiation

•Mutations can also arise spontaneously due to cellular errors.

•Mutagens give rise to cancer cells.•There are a wide variety of mutagens which cause changes to our DNA:•Chemicals•UV radiation•Ionizing radiation

•Mutations can also arise spontaneously due to cellular errors.

Cancer CellsCancer Cells


•Cancer cells don’t respond normally to the body’s control mechanisms.

•They don’t heed the normal signals which regulate the cell cycle.

•Some don’t need growth factors to grow and divide, while other cancer cells even make their own.

•Cancer cells don’t respond normally to the body’s control mechanisms.

•They don’t heed the normal signals which regulate the cell cycle.

•Some don’t need growth factors to grow and divide, while other cancer cells even make their own.


•Many cancer cells also fails to exhibit what is known as density dependent inhibition--an external physical factor regarding mitosis that stops the division of crowded cells.

•Many cancer cells also fails to exhibit what is known as density dependent inhibition--an external physical factor regarding mitosis that stops the division of crowded cells.


•Normal cells usually divide 20-50x in the process of aging and then die.

•Cancer cells are seemingly immortal because they will continue to divide forever if they are given a continuous supply of nutrients.•HeLa cells.

•Normal cells usually divide 20-50x in the process of aging and then die.

•Cancer cells are seemingly immortal because they will continue to divide forever if they are given a continuous supply of nutrients.•HeLa cells.

•Cancer cells have a high mitotic index. That is with cancer, there are often more cells undergoing mitosis compared to the number not undergoing mitosis.

•Cancer cells have a high mitotic index. That is with cancer, there are often more cells undergoing mitosis compared to the number not undergoing mitosis.


•Primary tumors are the original tumor in the organism.

•From there, tumors metastasize, or spread to other parts of the body where they form new, secondary tumors.

•Primary tumors are the original tumor in the organism.

•From there, tumors metastasize, or spread to other parts of the body where they form new, secondary tumors.

MetastasisMetastasis

•There is a multistep model that explains cancer development.

•Numerous changes must occur in the DNA in order for a cell to become cancerous.

•But before we begin, there are a few terms we need to discuss.

•There is a multistep model that explains cancer development.

•Numerous changes must occur in the DNA in order for a cell to become cancerous.

•But before we begin, there are a few terms we need to discuss.

Cancer DevelopmentCancer Development


•These terms will help you to understand what’s going on.•Apoptosis•Gate Keepers (Promoters)•Caretakers•p53•Oncogene•Proto-oncogene•Tumor Suppressor Genes

•These terms will help you to understand what’s going on.•Apoptosis•Gate Keepers (Promoters)•Caretakers•p53•Oncogene•Proto-oncogene•Tumor Suppressor Genes

ApoptosisApoptosis

•Apoptosis is programed cell death, and is a normal process that occurs in living organisms.

•Apoptosis is programed cell death, and is a normal process that occurs in living organisms.

Gate Keepers and Caretakers


•There are 2 general groups of tumor suppressor genes:•Gate Keepers (Promoters)•Caretakers

•There are 2 general groups of tumor suppressor genes:•Gate Keepers (Promoters)•Caretakers

•Gate Keepers act as “a set of breaks” on cellular proliferation.

•Caretaker genes are genes whose products protect the integrity of the genome by repairing damaged DNA.

•Gate Keepers act as “a set of breaks” on cellular proliferation.

•Caretaker genes are genes whose products protect the integrity of the genome by repairing damaged DNA.





•When gate keeper genes mutate or are damaged, they lose their ability to regulate cell division, kick-start repair mechanisms, or both.

•Mutations in these genes, therefore, allow mutations in other areas of the genome go unchecked, potentially giving rise to tumors.

•When gate keeper genes mutate or are damaged, they lose their ability to regulate cell division, kick-start repair mechanisms, or both.

•Mutations in these genes, therefore, allow mutations in other areas of the genome go unchecked, potentially giving rise to tumors.

•When caretaker genes mutate or are damaged, they lose their ability to repair DNA damage (or care for the genome).

•Thus, mutations in other areas of the genome accumulate and often give rise to tumors.•BRCA1 and BRCA2 genes.

•When caretaker genes mutate or are damaged, they lose their ability to repair DNA damage (or care for the genome).

•Thus, mutations in other areas of the genome accumulate and often give rise to tumors.•BRCA1 and BRCA2 genes.



BRCA1 17q21: This gene encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2009] - See more at: http://www.cancerindex.org/geneweb/BRCA1.htm#sthash.MEZYNuy1.dpuf

BRCA2 13q12.3: Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, Dec 2008] - See more at: http://www.cancerindex.org/geneweb/BRCA2.htm#sthash.7CqaTesC.dpuf

p53p53

•p53 is a tumor suppressor gene known as the “guardian of the genome”-it acts as a gate keeper.•The p53 gene makes p53 protein which does many different things.•It can arrest cell proliferation by holding the cell cycle at the G1/S checkpoint when DNA damage is recognized.

•p53 is a tumor suppressor gene known as the “guardian of the genome”-it acts as a gate keeper.•The p53 gene makes p53 protein which does many different things.•It can arrest cell proliferation by holding the cell cycle at the G1/S checkpoint when DNA damage is recognized.p53 17q13.1: This gene encodes a tumor suppressor protein containing

transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons (PMIDs: 12032546, 20937277). [provided by RefSeq, Feb 2013] - See more at: http://www.cancerindex.org/geneweb/TP53.htm#sthash.FG0ISunq.dpuf

•This protein is what binds to the DNA and regulates the expression of genes that control the cell cycle.

•p53 also activates repair proteins when the DNA has sustained damage.

•It can initiate apoptosis if the DNA damage is irreparable.

•This protein is what binds to the DNA and regulates the expression of genes that control the cell cycle.

•p53 also activates repair proteins when the DNA has sustained damage.

•It can initiate apoptosis if the DNA damage is irreparable.

p53p53

•Once activated, it functions as an activator for a number of different genes most notably, p21.

•When tumor suppressor genes such as p53 get damaged or undergo a mutation, they lose their ability to regulate cell proliferation.

•Once activated, it functions as an activator for a number of different genes most notably, p21.

•When tumor suppressor genes such as p53 get damaged or undergo a mutation, they lose their ability to regulate cell proliferation.

p53p53

Oncogenes and Proto-Oncogenes


•Proto-oncogene is the name given to the normal form of genes which promote and regulate cell proliferation.

•Oncogenes are mutant forms of proto-oncogenes that cause cancer.

•Proto-oncogene is the name given to the normal form of genes which promote and regulate cell proliferation.

•Oncogenes are mutant forms of proto-oncogenes that cause cancer.

•When a proto-oncogene undergoes a mutation that doesn’t get repaired, it becomes an oncogene.

•When a proto-oncogene undergoes a mutation that doesn’t get repaired, it becomes an oncogene.



•Under normal conditions, cells undergo a programmed form of cell death when damaged beyond repair (apoptosis).

•Under normal conditions, cells undergo a programmed form of cell death when damaged beyond repair (apoptosis).



•Activated oncogenes now promote cell proliferation by encoding proteins that increase expression of the normal genes involved in regulating the cell cycle.

•Thus, it is easy to see how damaged DNA leads to runaway cell division resulting in tumor growth.

•Activated oncogenes now promote cell proliferation by encoding proteins that increase expression of the normal genes involved in regulating the cell cycle.

•Thus, it is easy to see how damaged DNA leads to runaway cell division resulting in tumor growth.



•Tumor suppressor genes are found in the genomes of cells and work to inhibit cell division.

•They encode proteins that bind to various parts of the cell cycle machinery preventing runaway cell division.

•Tumor suppressor genes are found in the genomes of cells and work to inhibit cell division.

•They encode proteins that bind to various parts of the cell cycle machinery preventing runaway cell division.

Tumor Suppressor Gene Tumor Suppressor Gene

•How does this all fit in with mitosis?•Recall that the cell cycle is a carefully coordinated sequence of events that gives rise to genetically identical daughter cells.

•How does this all fit in with mitosis?•Recall that the cell cycle is a carefully coordinated sequence of events that gives rise to genetically identical daughter cells.

So What’s Going On?So What’s Going On?

•In its simplest form, cancer is runaway cell division; an out of control cell cycle.

•If unchecked, that initial rogue cell becomes a tumor--a group of cells with an aberrant cell cycle.

•In its simplest form, cancer is runaway cell division; an out of control cell cycle.

•If unchecked, that initial rogue cell becomes a tumor--a group of cells with an aberrant cell cycle.

CancerCancer

•There are genes for certain components of the pathway that act as tumor suppressors.

•The p53 gene codes for a transcription factor protein that promotes the synthesis of cell cycle-inhibiting proteins.

•There are genes for certain components of the pathway that act as tumor suppressors.

•The p53 gene codes for a transcription factor protein that promotes the synthesis of cell cycle-inhibiting proteins.

Cancer Cells p53Cancer Cells p53

•Some tumor suppressor proteins from p53 can repair damaged DNA, while others control the adhesion of cells to each other or to the extracellular matrix (density dependence).

•Still others are components of the cell-signaling pathway that inhibits the cell cycle.

•Some tumor suppressor proteins from p53 can repair damaged DNA, while others control the adhesion of cells to each other or to the extracellular matrix (density dependence).

•Still others are components of the cell-signaling pathway that inhibits the cell cycle.



•Normal p53 acts to control tumor formation using two mechanisms:•1. It activates p21 in response to DNA damage/stress.

•2. It controls tumor formation by inducing apoptosis.

•Normal p53 acts to control tumor formation using two mechanisms:•1. It activates p21 in response to DNA damage/stress.

•2. It controls tumor formation by inducing apoptosis.

•Most notably, p53 expression activates p21 whose protein product halts the cell cycle at G1 and S by binding to and inhibiting the cyclin-dependent kinases needed by the S phase.

•This is the halt step that allows time for the cell to repair the DNA.

•Most notably, p53 expression activates p21 whose protein product halts the cell cycle at G1 and S by binding to and inhibiting the cyclin-dependent kinases needed by the S phase.

•This is the halt step that allows time for the cell to repair the DNA.

1. p21 Activation1. p21 Activation

•Under normal conditions, p53 activates an inhibitor gene (p21) when DNA is damaged.

•As a result, p21 protein arrests the cell cycle and prevents cell proliferation.

•We don’t want a damaged cell dividing.

•If p53 function is lost, the p21 gene is not activated and p21 protein will not be available to act as the stop signal for cell division.

•Under normal conditions, p53 activates an inhibitor gene (p21) when DNA is damaged.

•As a result, p21 protein arrests the cell cycle and prevents cell proliferation.

•We don’t want a damaged cell dividing.

•If p53 function is lost, the p21 gene is not activated and p21 protein will not be available to act as the stop signal for cell division.


•Since the p21 protein is not available and there is no stop signal for cell division, the cell will continue through the cell cycle despite damage to DNA.

•An increase in mutant cell proliferation (tumor formation) often results.

•Since the p21 protein is not available and there is no stop signal for cell division, the cell will continue through the cell cycle despite damage to DNA.

•An increase in mutant cell proliferation (tumor formation) often results.


•p53 also activates expression of a group of miRNAs that act to inhibit the cell cycle.

•It can also directly turn on genes involved in DNA repair.

•When the DNA is beyond repair, it activates suicide genes stimulating apoptosis.

•p53 also activates expression of a group of miRNAs that act to inhibit the cell cycle.

•It can also directly turn on genes involved in DNA repair.

•When the DNA is beyond repair, it activates suicide genes stimulating apoptosis.


2. Induction of Apoptosis2. Induction of Apoptosis

•2. When a cell is damaged beyond repair, a normal-functioning p53 gene acts to induce cell death (apoptosis) and stops the cell from proliferating.•The immune system recognizes the dead cell and cleans it up.

•2. When a cell is damaged beyond repair, a normal-functioning p53 gene acts to induce cell death (apoptosis) and stops the cell from proliferating.•The immune system recognizes the dead cell and cleans it up.

•For example, exposure to UV light can damage DNA. This triggers the signaling pathway--through p53--that blocks the cell cycle until the damage has been repaired. •If the damage cannot be repaired, apoptosis is stimulated.

• If p53 does not act this way, the damage could contribute to the formation of a tumor as a result of the chromosomal abnormalities and cell division would perpetuate the abnormality.

•For example, exposure to UV light can damage DNA. This triggers the signaling pathway--through p53--that blocks the cell cycle until the damage has been repaired. •If the damage cannot be repaired, apoptosis is stimulated.

• If p53 does not act this way, the damage could contribute to the formation of a tumor as a result of the chromosomal abnormalities and cell division would perpetuate the abnormality.


•Thus, we can see how p53 acts as a gate keeper and is involved in a number of different pathways to prevent a cell from passing on mutations.

•Thus, we can see how p53 acts as a gate keeper and is involved in a number of different pathways to prevent a cell from passing on mutations.

Cancer Cells and p53Cancer Cells and p53

•Another group of proto-oncogenes belongs to the Ras is a family of genes.

•When a mutation occurs in a Ras gene, it can become an oncogene and possibly result in the formation of a tumor.

•Another group of proto-oncogenes belongs to the Ras is a family of genes.

•When a mutation occurs in a Ras gene, it can become an oncogene and possibly result in the formation of a tumor.

RasRas

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•Ras genes code for G-proteins that relay signals from growth factor receptors on the plasma membrane to a cascade of protein kinases.

•At the end of the pathway is the synthesis of a protein that stimulates the cell cycle.

•Ras genes code for G-proteins that relay signals from growth factor receptors on the plasma membrane to a cascade of protein kinases.

•At the end of the pathway is the synthesis of a protein that stimulates the cell cycle.

RasRas

•Under normal conditions, the pathway will not operate unless triggered by the appropriate growth factor.

•Under normal conditions, the pathway will not operate unless triggered by the appropriate growth factor.

RasRas

•Certain mutations in the ras gene lead to production of a hyperactive Ras protein that triggers the kinase cascade in the absence of growth factor.

•This then turns on genes associated with cell growth and differentiation.

•Certain mutations in the ras gene lead to production of a hyperactive Ras protein that triggers the kinase cascade in the absence of growth factor.

•This then turns on genes associated with cell growth and differentiation.

RasRas

•Since these signals result in cell growth and mitosis, overactive Ras signaling can lead to cancer.

•Since these signals result in cell growth and mitosis, overactive Ras signaling can lead to cancer.

RasRas

•There are a number of other genes that have been shown to play a role in caring for the genome and suppressing tumor formation.

•The study of these genes and their proteins have enabled us to better understand the cell cycle and how it works.

•There are a number of other genes that have been shown to play a role in caring for the genome and suppressing tumor formation.

•The study of these genes and their proteins have enabled us to better understand the cell cycle and how it works.

The TakeawayThe Takeaway

Documents

The Cell Cycle Gone Awry Cancer and Mitosis. Mutagens give rise to cancer cells. There are a wide variety of mutagens which cause changes to our DNA: