Apoptosis regulators and their role in tumorigenesis.

Abstract

Apoptosis is the most predominant form of physiological cell death. There are various diseases linked with suppression of apoptosis, including cancer, viral infections, and autoimmune disorders. Recognition and phagocytosis of apoptotic cells involves activation of a flippase in the apoptotic cells which allows them to express externalized phosphatidylserine. Another property of programmed cell death (PCD) is autophagy, or bulk degradation of cellular proteins. It is possible that PCD arose in unicellular organisms as a way of ensuring survival of at least some members of a clonal colony during periods of privation. Studies in C. elegans have identified genes controlling four aspects of PCD: (1) determination step, (2) execution of cell death, (3) engulfment of the dying cell, (4) degradation of engulfed cell DNA. There are three genes involved in the execution step, one encoding a killer protein that is a member of the cysteine aspartyl protease, or “caspase” family. The Ced-3 caspase is homologous to interleukin-1 converting enzyme, and the mammalian homologue to Ced-9 (a death-inhibiting protein) is Bcl-2. Caspase over-reactivity promotes cellular suicide, and this may be the basis for degenerative disorders such as Huntington’s disease and Alzheimer’s disease. Caspase inactivation may promote oncogenesis. Cytochrome c release from mitochondria during cell death is involved with triggering the effector machinery of apoptosis, where it is one factor implicated in activation of caspase-3 by caspase-9. The IAP protein family suppresses apoptosis through caspase inhibition, and cIAP-2 is activated in MALTomas. Mammalian Bcl-2 has anti- and pro-apoptotic processes. Mammalian pro-apoptotic Bcl-2 family members include Bax, Bak and Bik. There are cell death receptors, including the tumor necrosis factor (TNF) receptor superfamily. The receptors’ ligands comprise another related family that includes FasL/CD95L. CD95 receptor activation leads to autoactivation of various caspases. Naturally occurring inhibitors of CD95/TNF-R1 death signaling include FLIPs (Fas-associated death domain-like inhibitory proteins). A certain FLIP is over expressed in melanoma. Newly discovered TRAIL (TNF-related apoptosis-inducing ligand) receptors trigger a variety of cellular responses depending on cell type and context, including T cell activation and stimulation, proliferation, differentiation, survival and apoptotic cell death. There is resistance to TRAIL-induced apoptosis in neuroectodermal brain tumor cells. A number of oncoproteins induce apoptosis when over expressed in cells. One is c-Myc, which induces apoptosis through its action as a transcription factor, although c-Myc also has proliferative effects. The Bcl-2 family member Bax is a target of c-Myc. Another family member, Bak, is over expressed in colorectal adenocarcinoma. Additionally, c-Myc activates p53, which is encoded by the p16 tumor suppressor gene. The p53 tumor suppressor gene is functionally inactivated in 70 percent of human tumors. A germ line mutation in p53 results in Li-Fraumeni syndrome. Loss of tumor suppressor Rb function may contribute to p53-induced apoptosis, and many tumors display mutations in both Rb and p53. Any lesion that activates the mitogenic pathway will prove lethal through the c-Myc pathway if the affected cell and its progeny outgrow the paracrine environment enabling their survival. On the other hand, Bcl-2 effectively suppresses c-Myc induced apoptosis without significantly affecting the proliferative ability of c-Myc, thus explaining why co-expression of c-Myc and Bcl-2 induces lymphoma.—Hans E. Grossniklaus