Oncogenes and Tumor Suppressors: The Yin-Yang of Cellular Transformation

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Normal cell proliferation and differentiation are tightly controlled by genes that respond to growth signals and promote cell division, and those that restrict growth, turning off proliferation and promoting quiescence and differentiation. Growth promoting genes are called proto-oncogenes, while growth restricting genes are known as tumor suppressors.

Transformation of normal cells into tumor cells results when cell growth occurs in an autonomous and unrestricted manner. The underlying cause of this phenomenon is usually a combination of increased activity of oncogenes and/or decreased activity of tumor suppressor genes.

Oncogenes were originally discovered in oncogenic retroviruses such as RSV (Src), MC29 (Myc), Avian Erythroblastosis Virus (ErbB), and Harvey and Kirsten Sarcoma Viruses (H-Ras, K-Ras), but they are also present in DNA viruses such as SV40 (T Antigen), Adenovirus  (E1A), and HPV (E7 protein)7. It turned out that the retroviral oncogenes were actually captured cellular genes that were mutated by the virus or activated inappropriately by insertion into the host cell genome. Thus these oncogenes are mutated or altered forms of normal cellular genes, called proto-oncogenes. The DNA viruses, on the other hand, contain their own oncogenes as part of their genomes.

Proto-oncogenes are involved in normal cell processes such as growth factor signaling, stimulating cell division, inhibiting differentiation, and preventing apoptosis. Proto-oncogenes can be converted to oncogenes by a number of mechanisms including mutations that cause increased (constitutive) activity or stability, increased transcription, gene amplification, a chromosome translocation resulting in aberrant expression, or a chromosome translocation resulting in an oncogenic fusion protein. A gain-of-function in one allele (single hit) is often sufficient to cause transformation because mutations in oncogenes have a dominant effect7,8. Types of oncogenes include growth factors, receptor tyrosine kinases, G-proteins, adapter proteins, non-receptor tyrosine kinases, serine-threonine kinases, transcription factors, and lipid kinases7.

Tumor suppressor genes and proteins regulate cell division and drive apoptosis in normal cells1,6. Transformation by mutation of tumor suppressor genes typically requires loss-of-function in both alleles (2 hits). However, there is a gene dosage continuum for many tumor suppressor genes, rendering cells increasingly susceptible to transformation by subsequent mutations in other tumor suppressors or oncogenes1.

Rb was the first tumor suppressor gene to be discovered by tracing the occurrence and heritability of childhood retinoblastoma1. Next came p53, which has become the most studied of all the tumor suppressor genes3. Another familial form of cancer, Li-Fraumeni Syndrome, played a key role in the identification of p53 as a tumor suppressor3.

Tumor suppressor genes and proteins restrict cell division, induce and promote apoptosis, aid in repairing DNA damage, and inhibit metastasis1,6. Some tumor suppressors employ more than one mechanism to prevent transformation and tumorigenesis.  Other genes that have since been identified as tumor suppressors include APC, ARF, CD95 (FAS), BRCA1 and 2, and PTEN, among many others1,6.

Both oncogenes and tumor suppressors are attractive targets for cancer therapy. Oncogene-specific treatments have been primarily based on monoclonal antibodies or kinase inhibitors8. Among the most successful to date are trastuzumab for HER2+ breast cancer, and imatinib which inhibits the kinase activity of the Bcr/Abl fusion protein in chronic myeloid leukemia8. Emerging targets for cancer therapy are tyrosine phosphatase oncogenes2, histone methyl transferases and other epigenetic tumor suppressors5, and microRNAs, which include targets with both oncogene and tumor suppressor activities4.

 

Oncogenes and Tumor Suppressor Genes represent the Yin-Yang of cell growth regulation and transformation

Oncogenes and Tumor Suppressor Genes represent the Yin-Yang of cell growth regulation and transformation. Oncogenes (left side, green) drive cells into the cell cycle, promote proliferation, and suppress differentiation and apoptosis. Tumor Suppressors (right side, red) suppress progression through the cell cycle, and promote differentiation and apoptosis. When the balance of these two forces is perturbed by increased activity of one or more oncogenes, and/or decreased activity of one or more tumor suppressors, transformation occurs and cells are able to proliferate autonomously and without restriction.

References

1. Berger AH, Knudson AG, Pandolfi PP. 2011. A continuum model for tumour suppression. Nature. Aug 10;476(7359):163-9.

2. Frankson R, Yu ZH, Bai Y, Li Q, Zhang RY, Zhang ZY. 2017. Therapeutic Targeting of Oncogenic Tyrosine Phosphatases. Cancer Res. Nov 1;77(21):5701-5705.

3. Levine AJ, Oren M. 2009. The first 30 years of p53: growing ever more complex. Nat Rev Cancer. Oct;9(10):749-58.

4. Lujambio A, Lowe SW. 2012. The microcosmos of cancer. Nature. Feb 15;482(7385):347-55.

5. Spannhoff A, Sippl W, Jung M. 2009. Cancer treatment of the future: inhibitors of histone methyltransferases. Int J Biochem Cell Biol. Jan;41(1):4-11.

6. Sun W, Yang J. 2010. Functional mechanisms for human tumor suppressors. J Cancer. Sep 15;1:136-40.

7. Vogt PK. 2012. Retroviral oncogenes: a historical primer. Nat Rev Cancer. Sept;12(9):639-48.

8. Weinstein IB, Joe AK. 2006. Mechanisms of disease: Oncogene addiction--a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. Aug;3(8):448-57.