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BIOLOGY 445 Lecture 5: chemotherapy pharmacology 4

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School
Bloomsburg University
Department
Biological Allied Health Sci
Course
BIOLOGY 445
Professor
Schwing

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Document Summary

Lecture 15: chemotherapy 4: define oncogenes and tumor suppressor genes, proto-oncogenes are genes that normally help cells grow. When a proto- oncogene mutates (changes) or there are too many copies of it, it becomes a. bad gene that can become permanently turned on or activated when it is not supposed to be. When this happens, the cell grows out of control, which can lead to cancer. This bad gene is called an oncogene: oncogenes, proto-oncogenes. Increase cell proliferation: speed up cell division, activating mutation, erbb2(her2/neu) growth factor receptor, bcr-abl philadelphia chromosome, tk, tumor suppressor genes, decrease cell proliferation, slow down cell division, repair dna. Inactivating mutation: tp53- g1/s arrest; apoptosis, brca2- dna repair, tumor suppressor genes are normal genes that slow down cell division, repair. Dna mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death).

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Related Questions

You are interested in studying the origins of cancer and join a research lab to do so. You find that many cancer cell lines have mutations in the gene DRG1. You further investigate the mutations to DRG1 and find that some of the cell lines have mutations that affect expression of DRG1, so that no DRG1 mRNA is made in these cells, while other cell lines have mutations that lead the cells to produce a non-functional DRG1 protein.

a) Is DRG1 a proto-oncogene or a tumor suppressor? Explain your reasoning.

b) Your labmates propose several hypotheses about the possible role for DRG1 in normal cells. For each hypothesis, state whether or not you think it makes sense and explain your reasoning. a. DRG1 normally acts to repair DNA damage. b. DRG1 is a receptor for a mitogen (a signaling molecule that promotes cell division)

c. DRG1 is a receptor for a signaling molecule that causes apoptosis (programmed cell death).

QuestionGroup: #21 Gene expression 2

Assigned as

Homework

21

The direct end result of gene expression is which of the following?

A

Amino acids

B

Translation

C

Proteins

D

Carbohydrates

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QuestionGroup: #22 Mutation

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22

Which of the following is the ways in which nucleotide mutations lead to altered proteins?

A

One nucleotide is substituted by another nucleotide, which can cause an early stop codon to be incorporated into the amino acid sequence resulting in a truncated protein.

B

One nucleotide is replaced by another nucleotide, which can change an amino acid in the protein sequence

C

Nucleotides are inserted into a nucleotide sequence causing a frameshift in the sequence.

D

All three choices may cause mutations.

Unanswered

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QuestionGroup: #23 Mutation 2

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23

Mutations are the result of which of the following?

A

Change in the normal nucleotide sequence in the DNA directly resulting in different carbohydrates

B

Change in the normal nucleotide sequence in the DNA directly resulting in different proteins

C

Change in the order of transfer RNA to messenger RNA so that the transfer RNA take over the role of Messenger RNA

D

Primarily an alteration in the sequence of nucleotides in the abnormal proteins

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QuestionGroup: #24 Cell division

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24

There are two major kinds of cell division. Which of the following plays a major role in promoting genetic diversity?

A

Meiosis since it causes the cells to make more daughter cells than mitosis

B

Mitosis since it causes the cells to duplicate and eventually have mutations

C

Meiosis since it causes the DNA sequences to be separated into new patterns in the daughter cells.

D

Mitosis since it essential for the ovaries in humans to separate and duplicate

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QuestionGroup: #25 Cancer

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25

Genes that slow down or stop the cell cycle are called...

A

Apoptotic genes

B

Oncogenes

C

Restriction genes

D

Tumor suppressor genes

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QuestionGroup: #26 Cancer2

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26

The common theme in the development of all cancers is...

A

Mutation

B

Evolution

C

Infection

D

Syncopation

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QuestionGroup: #27 Genetics

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27

Punnett's square is which of the following?

A

Example of all possible combinations of alleles

B

Example of all possible combinations of chromosomes

C

Example of only certain combination of alleles since some will not be expressed.

D

Example of all possible combinations of DNA

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QuestionGroup: #28 Embryo development

Assigned as

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28

Which of the following is the end of the cleavage phase?

A

A fetus

B

Formation of a blastocyst

C

Implantation to the lining of the uterus

D

Fewer number of cells

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QuestionGroup: #29 Development of organ system

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29

For organs to be differentiated, which of the following is the first step?

A

Stem cells trigger the development of differentiated cells

B

Tissues assemble into organ systems such as blood

C

Tissue specific genes in stem cells are triggered

D

Differentiated cells form tissues

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QuestionGroup: #30 Development and society

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30

A pregnant mother ingests a chemical which her mother said would be great for the baby. When the baby was born, it had a large head and flippers for arms. What caused this phenotype?

A

The chemicals were teratogens which influenced oxidative phosphorylation causing the changes in the phenotype.

B

The chemicals influenced the expression of different stem cells.

C

There is no way to assume the chemicals caused the phenotype since we have no data on other mothers who took this medicine. It could have been purely by chance.

D

The chemicals were teratogens which caused the baby to show early signs of evolution.

Read the summary and answer questions in bold below:

In this post, we’ll be focusing on Tyler Jacks and his graduate student Francisco J. Sánchez-Rivera’s review, “Applications of the CRISPR-Cas9 system in cancer biology,” circa 2015 in Nature Reviews. So we understand the context of the authors, Jacks is the director of the Koch Institute for Integrative Cancer Research at MIT. His lab has a large mouse experimental component (MIT 2017). This sets the stage for the angle we’ll be reading from. In all, it’s a nice roundup of his and colleagues' cancer applications of CRISPR-Cas9 with great graphics, but leaves a bit desired in crossing the bridge from mouse to human.

Briefly, the CRISPR-Cas9 system stems from the prokaryotic immune system, where the RNA-guided DNA endonuclease Cas9 uses a single guide RNA (sgRNA) containing a CRISPR RNA (crRNA) and trans-activating crRNA (tracrRNA) that binds Cas9 and directs it to the genomic sequence of interest, adjacent to a photospacer adjacent motif (PAM). Cas9 causes a precisely-directed double-stranded break (DSB) in the DNA, that gets repaired via non-homologous end joining (NHEJ) or homology-directed repair (HDR).

With NHEJ, this can disrupt the gene by creating Indels: frameshifts and stop codons. In cancer, individual oncogenes or tumor suppressors can be targeted, or drug response modulators, or synthetic lethality genes. With a multiplexed knockout approach, combinatorial vulnerabilities and epistatic relationships can be assessed.

For gene modification via HDR, target single or double-stranded DNA can be introduced, resulting in precise gene knock-ins, with potential effects of introducing point mutations to mimic cancers, fluorescent reporters/synthetic tags can be created, conditional (Cre-lox/Flp-FRT) constructs can used to turn off/on a mutation, non-coding elements like enhancers/insulators/promoters can turn on proto-oncogenes, and ultimately, HDR can be used for gene correction.

With Cas9 and 2 sgRNAs, there can be genomic rearrangements, leading to deletions, inversions (like EML4-ALK), and translocations (like BCR-ABL).

Dead Cas9 (dCas), which lacks its endonuclease activity via mutation to its HNH and RuvC domains, can be used for reversible, transcriptional repression or activation of coding and non-coding genes, or chromatin modification, via an effector.

Much of the practical applications of CRISPR-Cas9 is in ES cells and mouse models, both germinal and somatic (GEMMs and nGEMMs). With this technology, a plethora of GEMM/nGEMM models of cancer can be created, some with the ability to turn on/off the Cas9 system, and multiplexed sgRNAs can help gain further understanding of multi-hit cancers. Patient derived xenografts (PDX) mice can be assayed with CRISPR-Cas9 to determine different treatment efficacies. Entire libraries of sgRNA can be screened in cancer cell lines for enrichment/depletion with Cas9, and dCas9-activators/repressors can be used for complementarity, both of which providing insights into drug targets, synthetic lethality, and chemotherapy modulators.

The delivery mechanisms for the system are diverse, and include plasmids, lentivirus, adenovirus, nanoparticles, hydrodynamic gene transfer, and protein-based. The authors also cite integrating Cas9 into the GEMMs, so it’s one less thing needed in the delivery vehicle. This of course would not be applicable to human.

Ultimately, human cancer treatment is the goal. Yes, we know the boundaries between ES/mice experimental models and human embryos have already been broken, with an international team targeting the autosomal dominant mutation in MYBPC3, which causes cardiac myopathy (Ledford 2017). But the current compromise position of CRISPR-Cas9 technology toward therapeutics and treatment, beyond basic science understanding, is using primary cells, organoids, PDX, or personalized GEMMs to create genetic and drug screens.

In theory, what would it take to bring CRISPR-Cas9 to the ultimate, targeted gene therapy via either NHEJ or HDR, in human cancer? Are there cancers that are better bets for CRISPR-Cas9 than others, delivery vehicles that are safer or better optimized? Is CRISPR-Cas9 really “on target” enough to introduce into a person, and how do we best assess?