p53 gene

Oncogenes and tumour suppressors are mutation targets promoting the onset and maintenance of cancer. Oncogenic mutations result in gain-of-function and deregulation of the function of the oncoprotein that they encode. Tumour suppressors act to run quality checking of DNA, keep cell cycle checkpoints, and shut down mitogenic signals; mutations in genes encoding tumour suppressors can lead to absence of these checks and give activated oncoproteins the chance to run riot in a cell. Co-incidence of mutations in oncogenes and tumour suppressor genes potentially leads to cancer.


Ras is a small G protein involved in a whole host of cellular functions. Mutation of Ras at a functional site can lead to a pleiotropic phenotype. Oncogenic Ras causes inappropriate signalling through its three pathways: MAPK, PI3K, and RalGEF. Signalling through the PI3K activates antiapoptotic Akt (PKB), which acts to promote cell survival. Signalling through RalGEF causes cell motility by formation of filopodia (Cdc42) and lamellipodia (Rac), which may be associated with metastasis. Signalling through MAPK actually causes the expression of some Ras signalling inhibitors (Sproutys, SPREDs, GAPs) which shuts down the signal in normal cells.

Myc is a transcription factor with more than 8000 transcription targets. Deregulated Myc leads to cell proliferation, but does not block apoptosis. Thus, it leads to a modest amount of growth before it is eradicated by apoptosis. Inhibition of apoptosis by antiapoptotic Bcl-xL is tumourigenic in cells expressing Myc highly. Additionally, Myc is thought to contribute to the tumour microenvironment, immune evasion, and inhibition of differentiation.

Ras and Myc work together by combining their abilities. Myc promotes cell proliferation and disfavours differentiation, and Ras inhibits apoptosis. The combination of the two means that cells are allowed to proliferate without triggering apoptosis. Ras actually activates Myc in normal cells - but in normal cells, activation is transient. Ras stabilises Myc by phosphorylation on S62 through MEK signalling, but also promotes its degradation by phosphorylation on T58 through PI3K signalling. The result is transient activation of Myc by Ras. Mutations which ultimately block phosphorylation at T58 will switch activation by Ras from a transient to a constitutive response.

Tumour suppressors

p53 is the so-called guardian of the genome. High Myc and oncogenic Ras cause stabilisation and activation of p53. p53 gets two bites at the cherry to combat the inheritance of damaged genomes: at the point of DNA damage, p53 arrests the cell until the DNA is repaired. p53 decides whether the cell enters senescence or apoptosis - its own state of post-translational modifications and the genomic context of its target genes (p53 is also a TF) on the genome in that particular cell both play a role in which way the scale tips. In this way, p53’s second bite of the cherry is the selection of apoptosis in cells whose DNA is damaged beyond repair.

Rb is the keeper of the G1/S checkpoint. Loss of both copies of the Rb gene leads to retinoblastoma. Familial retinoblastoma predisposes heterozygotes with a heightened risk of retinoblastoma by loss of heterozygosity - loss of their only functional copy. This can occur by mutation, but also by mitotic recombination, gene conversion, and nondisjunction. Cells null for Rb can still enter G0 phase, as p107 and p130 share some redundant functions with Rb.

NF1 displays the phenomenon of haploinsufficiency. Nf1-/- Schwann cells can be complemented for the wild-type by Nf1+/+ mast cells, but not Nf1+/- mast cells. The former gives the wild-type; the latter causes neurofibromas.

VHL suppresses the hypoxic response in normoxia by mediating the ubiquitin-associated degradation of HIF-1α in normoxia. Loss of VHL leads to a hypoxic response no matter the oxygen level.

Further reading:

  • Hanahan, D.; Weinberg, R.A. 2011. “Hallmarks of cancer: The next generation.” Cell 144:646-674.
  • Lowe, S.W.; Cepero, E.; Evan, G. 2004. “Intrinsic tumour suppression.” Nature 432:307-315.
  • Pylayeva-Gupta, Y.; Grabocka, E.; Bar-Sagi, D. 2011. “RAS oncogenes: Weaving a tumorigenic web.” Nature Reviews Cancer 11:761-774.
  • Soucek, L.; Evan, G.I. 2010. “The ups and downs of Myc biology.” Current Opinion in Genetics and Development 20:91-95.
  • Vousden, K.H.; Prives, C.; 2009. “Blinded by the light: The growing complexity of p53.” Cell 137:413-431.
  • Burkhart, D.L.; Sage, J. 2008. “Cellular mechanisms of tumour suppression by the retinoblastoma gene.” Nature Reviews Cancer 8:671-682.

World’s first pelvis transplant carried out in Italy.

The Centre for Orthopaedic Trauma (CTO) in Turin, Italy, has performed the world’s first pelvis transplant, an operation that saved the life of an 18-year-old suffering from osteosarcoma. The condition was considered inoperable and the boy responded quite well to 16 cycles of chemotherapy, but the doctors didn’t stop at the traditional treatment, racking their brains to find a definitive solution.

Osteosarcoma is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchymal origin (and thus a sarcoma) and that exhibits osteoblastic differentiation and produces malignantosteoid. Osteosarcoma is the most common histological form of primary bone cancer and it is most prevalent in children and young adults. It tend to occur at the sites of bone growth, presumably because proliferation makes osteoblastic cells in this region prone to acquire mutations that could lead to transformation of cells (RB gene and p53 gene are commonly involved).

In an 11.5-hour operation, surgeons removed half the patient’s pelvis along with part of his hip affected by the cancer, replacing them with a prosthetic made in the United States from titanium covered in tantalum, a non-corrosive metal mainly used in electronics components.

The operation had “an excellent outcome” and the patient is now undergoing intensive therapy to help him adapt to his new pelvis, the hospital said in a statement.

(Picture by Alexey Kashpersky).

Why don’t elephants get more cancer?

It’s called Peto’s paradox. The more times cells divide, the more risk there is that their DNA will be damaged. The bigger an organism is, the more times its cells have to divide to get to that size. Therefore, humans should be more prone to cancer than mice, and elephants more so than humans. But they aren’t. So there must be some way larger organisms protect their DNA from damage.

For 40 years, this has been an interesting hypothesis with zero evidence behind it. That is, until two separate studies discovered that elephants have extra copies of their TP53 gene. p53 is a massively important tumor suppressor. When cells detect DNA damage, they have to decide whether to switch on DNA repair to try and save themselves, or kill themselves to prevent that damage from spreading. p53 is where that decision gets made. In elephant cells, when the researchers induced DNA damage, they practically always went for the nuclear option–cell death. Elephants, presumably, have extras.

Neither study proposed a mechanism for exactly how this works. If I was working in their labs, I would hypothesize that having extra copies of p53 help it to remain functional when it’s damaged. This seems obvious, but p53 works strangely. It has to form a group of four of itself. If even one of those is damaged, the complex may not form and p53 can’t do its job, so a mutation in one of the usual two genes can totally screw you over. (Not that there’s going to be a quiz, but this type of mutation is called a dominant negative.) Having extra copies of the gene means there will be more good p53 floating around than bad, meaning it’s more likely to form a functional complex. But that’s just a guess, and it doesn’t explain how cells always choose to go the cell death route!

Source / 2 h/t to Nick Quintyne, who’s going to have to update his Cancer Bio lectures after this.

Representation of a complex between DNA and the protein p53

Tumor protein p53 is a protein that in humans is encoded by the TP53 gene. The p53 protein is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor, preventing cancer. As such, p53 has been described as “the guardian of the genome” because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene. The name p53 is in reference to its apparent molecular mass. 

There is apparently a protein called P53 and it monitors the integrity of DNA during cell division. If it finds something wrong, it will halt the cell cycle and stimulate special enzymes to repair it. If the DNA damage is irreparable P53 will prevent the cell from multiplying and causing cancer by directing the cell to kill itself. If that’s not poetic, I don’t know what is.