Preprint/Tumor suppressor

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Authors
Sarmoko, Adam Hermawan
About the Authors 

Sarmoko
AFFILIATION: Pharmacy, Jenderal Soedirman University , dr. Soeparno Street, Karangwangkal, Purwokerto 53123, Indonesia
0000-0002-1315-6085

Adam Hermawan
AFFILIATION: Pharmacy, Gadjah Mada University , Sekip Utara, Yogyakarta, Indonesia
0000-0001-5851-3691


Abstract

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A tumor suppressor gene encodes proteins that protect a cell from one step on the path to cancer. After Knudson hypothesizes "two-hit" hypothesis, our understanding of tumor suppressor gene has expanded quickly. Tumor suppressor genes can be classified as caretaker genes, gatekeeper genes, and landscaper genes. The pRB and p53 proteins are the products of tumor suppressor genes that are of most important in human carcinogenesis. The product of retinoblastoma (Rb) functions typically to inhibit cell cycle, whereas the TP53 tumor suppressor gene serves to identify DNA damage and to induce apoptosis. The growing discovery of tumor suppressor genes and putting them together into pathways and networks have brought significant insights into connecting new and exciting functions to existing ones. Recently, several promising strategies directed at tumor suppressor genes have emerged such as targeting p53 (including their regulators and the downstream) and synthetic lethality.

Introduction

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Unlike oncogenes, tumor suppressor genes generally follow the "two-hit hypothesis," which implies that both alleles that code for a particular protein must be affected before an effect is manifested. This is because if only one allele for the gene is damaged, the second can still produce the correct protein. In other words, mutant tumor suppressors' alleles are usually recessive whereas mutant oncogene alleles are typically dominant.

The two-hit hypothesis was first proposed by A.G. Knudson for cases of retinoblastoma.[2] Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics, implying that two independent genetic events were necessary. He recognized that this was consistent with a recessive mutation involving a single gene, but requiring biallelic mutation. Oncogene mutations, in contrast, generally involve a single allele because they are gain-of-function mutations.

There are exceptions to the "two-hit" rule for tumor suppressors, such as certain mutations in the p53 gene product. p53 mutations can function as a "dominant negative," meaning that a mutated p53 protein can prevent the function of normal protein from the un-mutated allele.[3]

Other tumor-suppressor genes that are exceptions to the "two-hit" rule are those that exhibit haploinsufficiency, including PTCH in medulloblastoma and NF1 in neurofibroma. An example of this is the p27Kip1 cell-cycle inhibitor, in which mutation of a single allele causes increased carcinogen susceptibility.[4]

Categories

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  • caretaker genes
  • gatekeeper genes
  • landscaper genes

Tumor suppressor in human

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relative occurance of different TSGs in different cancers

The first tumor-suppressor protein discovered was the retinoblastoma (pRb) in human retinoblastoma; however, recent evidence has also implicated pRb as a tumor-survival factor.

Another important tumor suppressor is the p53 tumor-suppressor protein encoded by the TP53 gene. Homozygous loss of p53 is found in 65% of colon cancers, 30–50% of breast cancers, and 50% of lung cancers. Mutated p53 is also involved in the pathophysiology of leukemias, lymphomas, sarcomas, and neurogenic tumors. Abnormalities of the p53 gene can be inherited in Li-Fraumeni syndrome (LFS), which increases the risk of developing various types of cancers.

PTEN acts by opposing the action of PI3K, which is essential for anti-apoptotic, pro-tumorogenic Akt activation.

As costs of DNA sequencing have diminished, many cancers have now been sequenced for the first time, revealing novel tumor suppressors. Among the most frequently mutated genes are components of the SWI/SNF chromatin remodeling complex, which are lost in about 20% of tumors.[5]

Other examples of tumor suppressors include pVHL, APC, CD95, ST5, YPEL3, ST7, and ST14.

Functions

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Tumor suppressors have a damping or repressive effect on the regulation of the cell cycle or promote apoptosis, and sometimes do both. The functions of tumor-suppressor proteins fall into several categories including the following:[6][7]

Cell cycle inhibiton

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Coupling the cell cycle to DNA damage. As long as there is damaged DNA in the cell, it should not divide. If the damage can be repaired, the cell cycle can continue.

DNA repair

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DNA repair proteins are usually classified as tumor suppressors as well, as mutations in their genes increase the risk of cancer, for example, mutations in HNPCC, MEN1 and BRCA. Furthermore, the increased mutation rate from decreased DNA repair leads to increased inactivation of other tumor suppressors and activation of oncogenes.[8]

Inducing apoptosis

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If the damage cannot be repaired, the cell should initiate apoptosis (programmed cell death) to remove the threat it poses for the greater good of the organisms produced

Metabolism regulation

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Cell-cell adhesion

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Some proteins involved in cell adhesion prevent tumor cells from dispersing, block loss of contact inhibition, and inhibit metastasis. These proteins are known as metastasis suppressors. [10][11]

Signal transduction

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Therapeutic targeting

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Targeting p53

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Synthetic lethality

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See also

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References

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  1. Wodak, S. J.; Mietchen, D.; Collings, A. M.; Russell, R. B.; Bourne, P. E. (2012). "Topic Pages: PLOS Computational Biology Meets Wikipedia". PLOS Computational Biology 8 (3): e1002446. doi:10.1371/journal.pcbi.1002446. PMID 22479174. PMC 3315447. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3315447/. 
  2. Knudson Jr, A. G. (1971). "Mutation and Cancer: Statistical Study of Retinoblastoma". Proceedings of the National Academy of Sciences of the United States of America 68 (4): 820–823. doi:10.1073/pnas.68.4.820. PMID 5279523. PMC 389051. //www.ncbi.nlm.nih.gov/pmc/articles/PMC389051/. 
  3. Baker, S. J.; Markowitz, S.; Fearon, E. R.; Willson, J. K.; Vogelstein, B. (1990). "Suppression of human colorectal carcinoma cell growth by wild-type p53". Science 249 (4971): 912–915. doi:10.1126/science.2144057. PMID 2144057. 
  4. Fero, M. L.; Randel, E.; Gurley, K. E.; Roberts, J. M.; Kemp, C. J. (1998). "The murine gene p27Kip1 is haplo-insufficient for tumour suppression". Nature 396 (6707): 177–180. doi:10.1038/24179. PMID 9823898. PMC 5395202. //www.ncbi.nlm.nih.gov/pmc/articles/PMC5395202/. 
  5. Shain, A. H.; Pollack, J. R. (2013). "The spectrum of SWI/SNF mutations, ubiquitous in human cancers". PLOS ONE 8 (1): e55119. doi:10.1371/journal.pone.0055119. PMID 23355908. PMC 3552954. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3552954/. 
  6. Sherr, C. J. (2004). "Principles of tumor suppression". Cell 116 (2): 235–246. doi:10.1016/s0092-8674(03)01075-4. PMID 14744434. 
  7. Sun, W.; Yang, J. (2010). "Functional mechanisms for human tumor suppressors". Journal of Cancer 1: 136–140. doi:10.7150/jca.1.136. PMID 20922055. PMC 2948218. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2948218/. 
  8. Markowitz, S. (2000). "DNA repair defects inactivate tumor suppressor genes and induce hereditary and sporadic colon cancers". Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology 18 (21 Suppl): 75S–80S. PMID 11060332. 
  9. Chen, C. Y.; Chen, J.; He, L.; Stiles, B. L. (2018). "PTEN: Tumor Suppressor and Metabolic Regulator". Frontiers in Endocrinology 9: 338. doi:10.3389/fendo.2018.00338. PMID 30038596. PMC 6046409. //www.ncbi.nlm.nih.gov/pmc/articles/PMC6046409/. 
  10. Yoshida, B. A.; Sokoloff, M. M.; Welch, D. R.; Rinker-Schaeffer, C. W. (2000). "Metastasis-suppressor genes: A review and perspective on an emerging field". Journal of the National Cancer Institute 92 (21): 1717–1730. doi:10.1093/jnci/92.21.1717. PMID 11058615. 
  11. Hirohashi, S.; Kanai, Y. (2003). "Cell adhesion system and human cancer morphogenesis". Cancer Science 94 (7): 575–581. doi:10.1111/j.1349-7006.2003.tb01485.x. PMID 12841864.