Question

In this discussion you will explore the role that genetics play in cancer. What role do these genes, and one gene in particular, normally play in cell division, and what happens when they gain mutations? This will help you better understand the molecular and cellular basis of cancer.

You should spend approximately 3 hours on this assignment.

Instructions

1. For your initial post, you will choose a gene that is commonly mutated in cancer (Gene Assignments: RAD9, C-KIT, EGFR, P53, HER2, RAS).
   • Start your discussion post with a summary paragraph on the major groups of genes that when mutated can cause cancer, and include the types of mutations that can change their protein structure.
   • Your next paragraph will focus on your gene of choice. You should find one to two reliable sources that discuss that gene. Focus on the group of cancer-causing genes that this gene belongs to, its normal function, and why the mutation can lead to the cell cycle becoming out of control.
   • Is your mutated gene inherited, or does it become mutated throughout a person’s lifetime?
   • If you could develop a drug that treats cancer caused by your mutated gene, how would the drug work? Would the drug damage non-cancerous cells as well? Explain

Answer 1

P53 gene

P53 mainly promotes cell cycle arrest, DNA repair and, if the damage is anbnormally wide, apoptosis. also known as the Guardian of the Genome In humans, the TP53 gene is located on the short arm of chromosome 17

DNA damage and repair

p53 plays a role in regulation or progression through the cell cycle, apoptosis, and genomic stability by means of several mechanisms:

• It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging.[30]
• It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition—if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.
• It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable.
• It is essential for the senescence response to short telomeres.

p53 pathway: In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.

If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome.

The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype

Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging. Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option.

Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it.

Many researchers believe the emerging science of gene therapy holds the key. A gene therapy treatment based on restoring p53 could be safely combined with traditional cancer treatments such as surgery, chemotherapy or radiation therapy to increase the overall effectiveness of the treatment plan.

RAS gene

All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells (cellular signal transduction). Ras is the prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and regulate diverse cell behaviours.

When Ras is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation and survival. Mutations in ras genes can lead to the production of permanently activated Ras proteins. As a result, this can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals.

Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer.

The 3 Ras genes in humans (HRas, KRas, and NRas) are the most common oncogenes in human cancer; mutations that permanently activate Ras are found in 20% to 25% of all human tumors and up to 90% in certain types of cancer (e.g., pancreatic cancer). For this reason, Ras inhibitors are being studied as a treatment for cancer and other diseases with Ras overexpression.

Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumors. It is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a possible method to inhibit certain cancer types. Ras point mutations are the single most common abnormality of human proto-oncogenes. Ras inhibitor trans-farnesylthiosalicylic acid (FTS, Salirasib) exhibits profound anti-oncogenic effects in many cancer cell lines.

Ras-targeted cancer treatments

Reovirus was noted to be a potential cancer therapeutic when studies suggested it reproduces well in certain cancer cell lines. It replicates specifically in cells that have an activated Ras pathway (a cellular signaling pathway that is involved in cell growth and differentiation). Reovirus replicates in and eventually kills Ras-activated tumour cells and as cell death occurs, progeny virus particles are free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until all tumour cells carrying an activated Ras pathway are destroyed.

Thank You!