The role of the apoptotic machinery in tumor suppression

Abstract

Multicellular organisms have evolved processes to prevent abnormal proliferation or inappropriate tissue infiltration of cells, and these tumor suppressive mechanisms serve to prevent tissue hyperplasia, tumor development, and metastatic spread of tumors. These include potentially reversible processes such as cell cycle arrest and cellular senescence, as well as apoptotic cell death, which in contrast eliminates dangerous cells that may initiate tumor development. Tumor suppressive processes are organized as complex, extensive signaling networks, controlled by central "nodes." These "nodes" are prominent tumor suppressors, such as P53 or PTEN, whose loss is responsible for the development of the majority of human cancers. In this review we discuss the processes by which some of these prominent tumor suppressors trigger apoptotic cell death and how this process protects us from cancer development.

Figure 1.

Apoptosis can be initiated by activation of two distinct, albeit ultimately converging, pathways, the “Bcl-2-regulated pathway” (left; also known as the “stress” or “mitochondrial” pathway) and the “death receptor pathway” (right). As the name suggests, protein–protein interactions between members of the Bcl-2 family govern activation of the Bcl-2-regulated pathway, whereas binding of their cognate ligands activates the death receptors (e.g., FAS, TNF-R1). Cellular demolition is performed by the effector caspases that act downstream of both pathways. Proteins that have been identified as suppressors or oncogenes are indicated in red or green, respectively.

Figure 2.

The tumor suppressor P53 acts as a transcriptional regulator. It has the capacity to activate diverse cellular processes. Stimulus and cell type-specific effects determine which particular effector pathway(s) will dominate.

Figure 3.

PTEN acts as the endogenous antagonist of the PI3K-regulated growth pathway. PTEN breaks down the key signaling intermediate PIP₃, thereby inhibiting downstream signaling mediated by AKT and TOR. Thus, PTEN negates PI3K’s ability to drive proliferation, facilitate nutrient mobilization, and inhibit apoptosis.

Figure 4.

CYLD acts proximal to the membrane as a negative regulator of TNF-induced NF-κB signaling. The deubiquitinase activity of CYLD allows it to hydrolyze K63-linked ubiquitin chains, which are critical for the activity of multiple components within the NF-κB signaling network, and thereby acts as a suppressor by inhibiting proliferation and promoting apoptosis.

Figure 5.

PTPN12 is a recently described tumor suppressor with phosphatase activity. It negatively regulates signaling through multiple oncogenic receptor kinases, such as EGFR and HER2. By limiting the activity of these receptors, PTPN12 blocks their ability to promote proliferation, nutrient mobilization, and inhibit apoptosis.