3.2 Gatekeeper and Caretaker Overview

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There are two main categories of Tumor Suppressor Genes (TSGs): gatekeepers and caretakers. Gatekeepers control cell proliferation by regulating the cell cycle whereas caretakers maintain the integrity of cellular genetic material. Both types of TSGs are important in preventing tumorigenesis. 


 

Gatekeepers

 

Gatekeepers are genes encoding proteins that regulate cell proliferation. They act as guards that prevent cells from passing through cell cycle checkpoints by countering the progression of cellular growth and encouraging apoptosis. Gatekeepers are cell-type specific and normally prevent uncontrolled growth and potential progression of cancer. Before considering the effects of a dysfunctional gatekeeper gene, we must understand the carefully orchestrated regulation of the normal cell cycle.

 

The cell cycle is a highly regulated process, for which two major players are primarily responsible – cyclins and cyclin-dependent kinases (Cdks). Cyclins are a family of regulatory proteins that are present at varying concentrations throughout the cell cycle. The binding of cyclin to Cdk creates a cyclin-Cdk complex, which plays a role in the progression of cells through the specific stages of the cell cycle by regulating cell-cycle checkpoints. For a brief review of these proteins involved in regulating the cell cycle, watch this video.

 

Gatekeepers interact either directly or indirectly with these cyclin-Cdk complexes. Thus, deactivation of gatekeeper genes by mechanisms mentioned in the previous section, allows cells to bypass the cell cycle checkpoints, leading to unrestricted proliferation, differentiation, and immortality of tumor cells (1). Mutation of one gatekeeper gene predisposes an individual to cancer, while mutation of two gatekeeper genes often leads to neoplasia—new growth in excess of normal tissue. Often, one cell type will have several gatekeeper proteins (1). Various gatekeeper genes are listed in Table 3.2.1. Specific examples of gatekeeper genes (Rb, BRCA and APC) will be described in detail later on in this chapter.

 

Table 3.2.1. Various Tumor Suppressor Genes and their roles. Table adapted from Oliveira et al. 2005 (4).

Tumor Suppressor Gene

Category

Function

Rb1

Gatekeeper

Inhibition of cell cycle

p53

Gatekeeper/Caretaker

DNA repair; cell cycle and apoptosis regulator

BRCA1

Caretaker

DNA repair

ATM

Caretaker

DNA repair

MLH1

Caretaker

Mismatch repair

CDKN1B

Gatekeeper

Inhibition of cell cycle

MSH2

Caretaker

Mismatch repair

APC

Gatekeeper

Transcription inhibition of β-catenin

STK11 (LKB1)

Gatekeeper

Serine-threonine kinase signaling

CDH1

Gatekeeper

Cell adhesion

 

 

Caretakers

Caretaker genes, a second type of tumor suppressor gene, maintain and protect the integrity of the genome and may sometimes be referred to as "genome maintenance genes." In general, these genes are involved in DNA repair and help prevent accumulation of mutations. Caretaker mechanisms include DNA base excision repair, nucleotide excision repair, prevention of oncogenic chromosomal rearrangement, non-homologous end joining, mismatch repair and telomere  maintenance (Chapter 1).  Two examples are MLH1/MSH2, which are involved in DNA mismatch repair, and XP-A, which is involved in the nucleotide excision repair pathway (2,3). Additional examples of caretaker genes involved in cancer formation are listed in Table 3.2.1.

 

A faulty protein arising from a mutant caretaker gene can lead to certain genomic instabilities such as microsatellites, point mutations, or chromosomal instabilities (7). In humans, chromosomal instabilities, brought about by chromosomal rearrangement errors, are the cause of many hereditary predispositions to cancer. Mutations in caretakers could indirectly initiate tumour formation because the affected cells easily accumulate mutations due to impaired genome maintenance.  However, two knockouts in a caretaker gene, as well as other mutations within the cell, are required for tumour formation (5). 

 

Other Functions of Gatekeepers and Caretakers

In addition to their anti-cancer functions, gatekeeper and caretaker genes have been known to have an effect on senescence, especially later in life. Gatekeepers may induce aging, and caretakers are known to maintain telomeres. Dysfunctional gatekeepers and caretakers may thus lead not only to cancer but also to premature aging.

 

Overlaps between Gatekeepers and Caretakers

Some genes, such as p53 that will be discussed in the next section, fall into both categories. p53 is most often identified as a gatekeeper, since it is directly involved in cell cycle regulation and cellular proliferation. However, p53 also has many caretaker functions and is involved in DNA repair mechanisms.

 

Figure 3.2.1. Mutations in both caretaker and gatekeeper pathways lead to tumour initiation through a two-hit model. Dysfunctional caretaker genes can lead to rapid acquisition of mutations in several gatekeeper genes. Released under the Creative Commons Attribution-ShareAlike 4.0 International license (CC BY-SA 4.0).

 

Landscapers

Recently, a third group of tumor suppressor genes has been proposed. These are called "landscaper genes," and they encode products that help create environments that control cell growth. Landscapers were first discovered when lesions were found in cells surrounding tumour tissue in juvenile polyposis syndrome (JPS) (5). It was observed that the initiating lesions occurred not in the tumour cells, but rather in the surrounding stromal cells. Without functional copies of a landscaper gene, the microenvironment may become abnormal such that it promotes transformation of normal epithelial cells. Predicted mechanisms involving these landscaper genes include regulation of extracellular matrix proteins, cellular surface markers, cellular adhesion molecules, and growth factors (5). One possibility is that mutants in landscapers involved in regulating cell membranes may trigger chemokine release, leading to unregulated cellular proliferation. An example of a landscaper gene is PTEN, and some evidence suggests that Rb can also function as a landscaper (5,6).

 

References

1) Weinberg, R. (2010). The Biology of Cancer (1st ed.). Garland Science.

2) Deininger, P. (1999). Genetic instability in cancer: caretaker and gatekeeper genes. The Ochsner journal1(4), 206–9. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3145442&tool=pmcentrez&rendertype=abstract

3) Kinzler, K. W. (1999). Cancer-susceptibility genes. Gatekeepers and caretakers. Nature1(2), 121–125. doi:10.1046/j.1463-1326.1999.00023.x

4) Oliveira, A.M., Ross, J.S., Fletcher, J.A. (2005). Tumor suppressor genes in breast cancer: the gatekeepers and the caretakers.  Pathology Patterns Reviews, 124:S16–S28.

5) Macleod, K.  (2000).  Tumour suppressor genes.  Current Opinions in Genetics & Development.  10(1), 81-93. 

6) Stratakis, C.  Genetics of adrenocortical tumours: gatekeepers, landscapers and conductors in symphony.  TRENDS in Endocrinology and Metabolism.  14(9), 404-410.

7) Milinkovic, V. et al. (2012). Genomic instability and p53 alterations in patients with maglignant glioma. Experimental and Molecular Pathology 93, 200-206.