Tumor Suppressors and Oncogenes

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The cell cycle is a series of ordered events that occur in a cell between it’s initial formation and eventual duplication and division into two daughter cells. Cells in the human body normally reproduce up to ~50 times [1], doubling their number with each cell cycle. Stem cells provide a pool of dividing cells to replace those that have died.

Interphase, the period between cell divisions, is where most cells remain for at least 90% of the cell cycle. Interphase consists of three phases: G1 (for gap 1), S phase (for synthesis) and G2 (for gap 2). During G1, the cell undergoes rapid growth and metabolic activity, including production of RNA and synthesis of protein. For the cell to divide and produce an identical copy of itself, its genome must be duplicated. DNA replication occurs in S phase. During G2, cell growth continues and the cell prepares for division. Cell division or mitosis occurs in M phase.

In normal cells, during G1 there are specific genes that control the speed of the cell cycle. These genes, called tumor suppressors and oncogenes, are mutated (meaning damaged) in cancer cells and can result in uncontrolled reproduction. Additionally, unlike normal cells, cancer cells do not stop reproducing after ~50 divisions. Thus, a cancer is an uncontrolled proliferation of cells.

Tumor suppressors

Tumor suppressors are genes that either slow down cell division, DNA repair or cell death (a process known as apoptosis or programmed cell death). These processes are all interconnected. Throughout the cell cycle there are DNA damage checkpoints; if there is damage, DNA replication is paused while the damage is repaired. In the event that the damage cannot be repaired, the cell initiates apoptosis. When a tumor suppressor gene is mutated (increasing either their expression or function) and inactivated (meaning turned off; also referred to as “loss of function”), cells can grow out of control and lead to cancer. As of 2003, 174 tumor suppressor genes were identified [2], including:

The analogy is often made between tumor suppressors and the brakes on a car. Just as the brakes keep a car from going too fast, tumor suppressors keep the cell from dividing too quickly.

Oncogenes

In contrast to tumor suppressors that are inactivated, oncogenes are permanently activated. Oncogenes are mutated forms of genes called proto-oncogenes that normally control cell division and the degree of differentiation (a process by which cells acquire “a type”). When a proto-oncogene is permanently activated (meaning turned on; also referred to as “gain of function”) through mutation, it is called an oncogene. When this occurs, cell division happens too quickly and cells can grow out of control and lead to cancer.

Some classic examples of proto-oncogenes are:

Oncogenes are analogous to the accelerator on a car. Oncogenes “drive” the cell cycle, speeding up cell growth and division.

Two-hit hypothesis

In 1971, Alfred Knudson proposed the two-hit hypothesis for tumorigenesis [3]. While studying children with retinoblastoma (a cancer of the eye), Knudson noted differences between patients with inherited tumors and patients that appeared to have no susceptibility to the disease. Statistical analysis revealed that the fraction of cases not yet diagnosed in patients with the hereditary form of the disease decreased exponentially with age, suggesting that one mutational event caused the cancer.

His findings demonstrated that multiple mutational events or “hits” were necessary to cause cancer. Everyone has two copies of most genes, one from their mother and one from their father. Normally, one mutation is not enough for cancer to develop, unless you were born with it. This occurs with people who have familial cancer (meaning occurs in families). People who were born with a mutation in a tumor suppressor are predisposed to cancer and only need damage in the other copy for cancer to develop. Those born without the mutation require two mutational events to occur, statistically much less likely. However, there are cases where a single mutation is sufficient to cause an effect, notably the p53 gene.

The current view of cancer has built upon the two-hit hypothesis. Today, cancer is modeled as an accumulation of mutations in both tumor suppressors and oncogenes. Additionally, epigenetic changes (meaning something that affects a cell without changing its DNA sequence) [4] and microRNAs [5] play a role. Thus, a number of genetic and epigenetic alterations are thought to be required for tumor progression and the development of cancer.

The scope of this article is limited to a basic overview of the two general classes of genes that contribute to cancer. For a more information, Nature Milestones in Cancer highlights achievements made in cancer research since the end of the nineteenth century and provides historical perspective on how given concepts evolved.

References

  1. L Hayflick. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965 Mar;37:614-36.
    View abstract
  2. Yang and Fu. TSGDB: a database system for tumor suppressor genes. Bioinformatics. 2003 Nov 22;19(17):2311-2.
    View abstract
  3. AG Knudson. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820-3.
    View abstract
  4. AP Feinberg. The epigenetics of cancer etiology. Semin Cancer Biol. 2004 Dec;14(6):427-32.
    View abstract
  5. Calin and Croce. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006 Nov;6(11):857-66.
    View abstract
About the Author

Walter Jessen is a senior writer for Highlight HEALTH Media.

Comments

  1. I always find these reads interesting. It is interesting the fail safes the body has to protect itself. I did know they feel there a numerous assaults before the cancer cells form, thereby overriding all the stops along the way. It’s a strange feeling to sit on the examining table and be told your DNA is damaged. I remember thinking what on earth does that mean! I had no family history, no risks, I was 36..I kick boxed 4 times a week. I was in excellent shape and yet…

    On another topic, I saw some discussion on the 32 sequence related to the black plague and HIV, are you familiar with their studies of this? Interesting stuff. Now it seems some feel there are no connections, yet, why then are there some, that never contract full blown AIDS?

    I can not think of the man’s name at present, it’s been some years now, but his blood was being studied. I realize advancements in medicine have helped many to stave off the disease, not unlike Tamoxifen, and such trying to stave of recurrence of cancer. So many interesting studies being done, but still no where near a cure.

  2. The study you’re referring to identified a 32-base-pair deletion in the coding region of a gene called CCR5 (chemokine (C-C motif) receptor 5) that was found to confer a strong resistance to HIV in individuals with two copies of the allele (meaning mutated CXCR4 gene) and delayed AIDS progression in individuals with one copy. CCR5, also known as CXCR4, acts with the CD4 protein to support HIV entry into cells. CXCR4 is also highly expressed in tumor cells.

    The mutation was found at a very high frequency in the population and it was initially thought that some selection, possibly bubonic plague and smallpox, drove it’s spread. However, more recent work has shown no evidence for positive selection and that the pattern of genetic variation at the allele is similar to the rest of the genome.

    Yes, there are many interesting studies being done. The problem with cancer is that it’s not a single disease but a wide range of different diseases of which there are well over a hundred types.

  3. Yes, that was the study. Initially it sounded like they may well have made an interesting find and connection. Sadly, cancer is fraught with challenges to find a cure, or true prevention.

    Dr. Charles has an interesting post on HIV and some rather questionable research regarding a study being done.

    I have always felt they needed to look into the immune system on the prevention of cancers. Although, I am in no way a scientist, just an interested bystander.That said..boosting a normally funcitoning immune system is not a good idea from what I understand. That would be an interesting topic. People take supplements to do this, and yet strange things can happen from doing such things. People can develop temporary alopecia ( this happened to a friend of mine), and who knows what else. There has even been controversy over vitamin supplements. Thank you for your return comments. I think you have a great site here. I’m glad I’ve found you.

  4. Thanks for the compliment Chrysalis Angel, I’ve worked very hard on the site. I’m glad you continue to visit and hope I can continue to write articles that inform and engage you.