2010م - 1444هـ
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1. Introduction

The discovery of tumor suppressor genes, whose loss predisposes to tumor

development, has revolutionized the molecular analysis of cancer (1–3). By definition, tumor suppressor genes are genetically linked to a cancer. For example,

the retinoblastoma (RB) tumor suppressor was first identified as a gene that

was specifically lost in familial RB (4–6). The majority of tumor suppressors

4 Knudsen and Angus

has been identified based on linkage analysis and subsequent epidemiological

studies, however, initial understanding of their mode of action was relatively

limited. As the number of tumor suppressors has increased, understanding the

mechanism through which tumor suppressors function has become an important

aspect of cancer biology.

In general, tumors exhibit uncontrolled proliferation. This phenotype can

arise from loss of tumor suppressors that regulate progression through the cell

cycle (e.g., RB or p16ink4a) or upstream mitogenic signaling (e.g., NF1 or PTEN)

cascades (1,3,7–9). Thus, specific tumor suppressors can function to suppress proliferation. However, not all tumor suppressors act in this manner. For example,

mismatch repair factors (e.g., MSH2 or MLH-1) lost in hereditary nonpolyposis

colorectal cancer (HNPCC) function not to inhibit proliferation, but to prevent

further mutations (10–12). Additionally, other tumor suppressors have multiple functions, for example, p53 can function to either induce cell death or halt

cell-cycle progression (9,13).

Functional analysis of tumor suppressors relies on a host of methods to determine how or if they inhibit proliferation. Later, we will focus on methods that

have been used to assess the antimitogenic potential of the RB-pathway (2,3,7,

14). However, these same approaches are amenable to any tumor suppressor or

antimitogenic molecule.