Preprint/Tumor suppressor

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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

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. 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.

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.

Categories

• caretaker genes
• gatekeeper genes
• landscaper genes

Tumor suppressor in human

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.

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

Functions

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:

Cell cycle inhibiton

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

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.

Inducing apoptosis

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

• P53
• PTEN.

Cell-cell adhesion

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.

See also

• example

Wikipedia pages that should link here

• Tumor suppressor