Second year undergraduate essay written for the Cell Pathology module of the Biomedical Sciences course at the University of Oxford.
Essay title: How were tumour suppressor genes discovered and how do they work?
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How were tumour suppressor genes discovered and how do they work?
Activation of oncogenes and inactivation of tumour suppressor genes (TSG) represent two
types of genetic alteration that contribute to cancer development. While oncogenes drive
abnormal cell proliferation, TSG represent the opposite side of cell growth control by
restraining cell proliferation. Accordingly, loss or inactivation of TSG liberates cells from their
tumour-suppressing effects. This essay will illustrate the discovery of TSG followed by an
account of two common tumour suppressors, pRb and p53.
Discovery
The discovery of TSG began with studying cell hybrids and familial cancer that were hard to
reconcile with the already known oncogenes. The story begins with cell fusion studies
initiated by Henry Harris (1969), fusion of normal cells with cancer cells generated hybrid
cells that were incapable of tumourigenesis in animals, but some daughter cells of these
hybrids regained tumourigenicity with spontaneous loss of normal chromosomes. This
implied that cancer phenotype was recessive and it appeared that a certain gene, which
came to be the first TSG to be identified called the retinoblastoma (Rb) gene, from the
normal cell parent antagonised the cancer phenotype. However, criticisms pointed out that
elimination of both wild-type alleles is unlikely to happen in the short time period as in
early-onset cancers given the low mutation rate. This contradiction could not be resolved
until the study of retinoblastoma, a rare familial eye tumour, provided important insights.
The tumour syndrome appeared in two forms – sporadic and familial – corresponding to the
absence and presence of family history of retinoblastoma respectively. It was recognized
that familial retinoblastoma is inherited in a Mendelian dominant fashion, where half the
children of affected parents developed the disease. Although the pattern of inheritance
appears to be autosomal dominant, the mutations ought to be recessive since presence of
cancer-inducing alleles was insufficient for a cancer phenotype as shown in the cell fusion
studies, this means that development of retinoblastoma required additional events beyond
the inheritance of these alleles. Through kinetic studies, Knudson (1971) discovered that
familial retinoblastoma developed at a rate that was consistent with a single-random event,
whereas two random events were required for sporadic retinoblastoma to develop. He
therefore proposed the two-hit theory which speculated that the development of
retinoblastoma required two mutational events, one of which is inherited by patients of
familial retinoblastoma so retinal cells only need to eliminate the single remaining wild-type
allele of the Rb gene to permit tumourigenesis. In contrast, sporadic retinoblastoma is rare
as it only develops when both wild-type alleles are eliminated, by loss-of-function mutations
but also less specific but more probable mechanisms such as mitotic recombination
resulting in loss of heterozygosity (LOH). Finally, in 1986, isolation of the RB gene as a
molecular clone by Friend et al. following the localization of Rb gene to chromosome 13q14
through visualizing chromosomal deletions confirmed that it is consistently lost or mutated
in retinoblastomas, which firmly establishes the tumour suppressor theory. LOH in cancer
cells has been widely exploited to identify new TSG by positional cloning, some TSG were
also identified by their association with viral oncoproteins.
, In 2000, Hanahan and Weinberg identified six hallmarks of cancers and suggested that all
cancers develop by acquisition of all these characteristics through genetic alterations such
as TSG loss or inactivation.
In the following sections, two well-known TSG will be illustrated. First mentioned is the Rb
gene, elimination of which causes self-sufficiency in growth signals and insensitivity to anti-
growth signals; Next discussed is the p53 gene that allows cells to evade apoptosis and anti-
growth signaling when inactivated. Although not as well-understood, both genes may
contribute to other hallmarks too.
TSG example: Rb gene
The Rb gene is a gatekeeper that plays a pivotal role in the negative control of the cell cycle.
Protein Rb (pRb) produced from the Rb gene controls the passage of the cell cycle through
its restriction (R) point, which is when commitment occurs as the cell goes from the G1 to S
phase so it no longer requires growth factors to complete the cell cycle. In the
hypophosphorylated state, pRb blocks advancement of the cell through its R point by
inhibiting transcription of cell cycle genes by sequestering E2F transcription factors. When
prerequisites for cell cycle commitment are fulfilled, cyclin D and E activate cyclin-
dependent kinases (CDK)-4/6 and 2 respectively, which in turn hyperphosphorylate pRb to
relieve its inhibition on E2F hence allowing cell cycle progression.
Consequently, malfunctioning Rb causes uncontrolled cell proliferation hence
tumourigenesis. An extensive body of data shows that the pRb pathway is dysregulated in
many tumours mostly due to loss-of-function mutations, but also through promoter
methylation or functional inactivation by viral oncogenes like the HPV E7 protein. R point
dysregulation in some cancers may also result from alterations in other pRb regulators, such
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