The independence of the intrinsic pathway from the extrinsic pathway has been demonstrated in a series of gene knockout studies.
However, apoptosis can essentially be divided into two major pathways, extrinsic and intrinsic. Consequently, PARP converts DNA strand breaks into intracellular signals that activate DNA repair programs, but strong activation of PARP exhausts cellular ATP and causes necrotic cell death (see below). Zahid H. Siddik, in Cancer Drug Design and Discovery (Second Edition), 2014. Alterations of these checkpoint genes have been associated with failure of apoptosis and are thought to be causal events in the development of human cancer [23]. The downstream effect of p53 acetylation was determined by quantitation of PUMA, Bax, and p21 gene expression. Apoptosis signaling induced by p53 can be transduced along both the extrinsic and intrinsic pathways (Fig. Each of these isoforms arises as a result of alternative splicing of the primary mRNA transcript of the gene, BBC3. An open-label phase-I dose-finding study of APR-246 in hematological malignancies has also been reported [136]. The transcription factor p53 controls the expression of multiple apoptosis regulatory genes that participate in the mitochondrial or intrinsic pathway, as well as the death-inducing signaling complex receptors, which form part of the extrinsic apoptotic pathway. In the intrinsic pathway, by contrast, events in the nucleus activate apoptotic signaling, such as DNA damage caused by ultraviolet or ionizing (gamma) irradiation. Although p53-induced apoptosis usually requires transcriptional activation, it can also occur in a transcription-independent manner (discussed further in this chapter). FIGURE 20.28. However, a distinguishing feature is that the extrinsic pathway is mediated through caspase-8, whereas the intrinsic pathway involves caspase-9 (Fig. In extrinsic apoptotic signaling, death receptor ligation initiates apoptosis by either a type I (nonmitochondrial) or type II (mitochondrial) caspase activation cascade. 20.28).

Cancer cells have deleterious mutations in the genome but for some reason have suppressed the senescence and apoptosis pathways so that they continue to grow and divide. That being said, a subsequent study examined the subcellular localization and functional consequences of a GAPDH construct containing a nuclear localization signal (NLS-GAPDH). The mutation is also found in many cancers, including pancreatic and lung. DNA damage also activates PARP.

It exhibits a favorable pharmacokinetic profile and can induce p53-dependent biologic effects in tumor cells in vivo. J.J. Lemasters, in Comprehensive Toxicology, 2010.

One group is composed of members that, like BID (BCL-2-interacting domain death agonist), are proapoptotic and include BAX (BCL-2-associated x protein), BAK (BCL-2 antagonist killer 1), BAD (BCL-2 antagonist of cell death), BIM (BCL-2-interacting mediator of cell death), NOXA, and PUMA (p53-upregulated modulator of apoptosis) (Fig. The functions of these proteins are coordinated to activate or enhance potency of the effector caspase. The interaction of SNO-GAPDH with p300/CBP was demonstrated both in vitro and in vivo by affinity chromatography, coimmunoprecipitation, and by colocalization in macrophage nuclei. As mutant p53 is more amenable to this type of covalent modification than the wild-type p53 [134], PRIMA-1 and PRIMA-1Met are attractive compounds with a large therapeutic window. 12.1). The most common interactions are between tumor necrosis factor (TNF), TNF-related apoptosis-inducing ligands (TRAILs), or FasL ligands and, respectively, their cognitive receptors TNF-R1 (TNF receptor type 1), DR4 (TRAIL-R1) and DR5 (TRAIL-R2), or Fas (also known as Apo-1 or CD95) (Fig. The latter was determined by immunoprecipitation with an antiacetyl lysine antibody. PRIMA-1 (p53-reactivation and induction of massive apoptosis-1) and its methylated analog PRIMA-1Met (also known as APR246) are quinuclidine compounds that rescue the DNA-binding activity of a number of p53 mutants, and restoring the wild-type like function in vitro [132, 133]. The BH3-only proteins usually induce MOMP via oligomerization of Bax and Bak to form channels in the outer mitochondrial membrane. Defects in p53 and pRb Extend Cellular Life Span. To escape p53-dependent induction of apoptosis, many tumors, especially those from the gastrointestinal tract, have loss-of-function mutations for p53. The formation of this protein–DNA complex was blocked by GAPDH RNAi and by transfection of the GAPDHlysK160R mutant.

Ras, p53, and pRb are proteins that regulate senescence.

1-22) does not require ligation of a cell surface DR and can be triggered by a variety of cell stressors or by DNA damage that leads to activation of p53-upregulated modulator of apoptosis (PUMA).

The observed p53 acetylation could be blocked by transfection of the GAPDHlysK160R mutant.

Proapoptotic Bcl-2 family members translocate to mitochondria to induce cytochrome c release by mechanisms discussed above for the extrinsic pathway (Miyashita and Reed 1995; Oda et al. The original member BCL-2 was identified in non-Hodgkin lymphoma, but is present in many cell types and functions as a negative regulator of apoptosis. To defend the organism, tainted cells sacrifice themselves by starting the genetic program for senescence or apoptosis, thus entering premature senescence. By continuing you agree to the use of cookies. John J. Lemasters MD, PhD, in Molecular Pathology (Second Edition), 2018. 8.1, these findings suggest a sequential regulatory pathway, which begins with NO modification of GAPDH and ends with apoptosis. Damaged cells that bypass the senescence program and block apoptosis are called cancer. In contrast, the transcription-independent mechanism of apoptosis is relatively fast since the mechanism is simply dependent on translocation of p53 to the mitochondria and its negative interaction with antiapoptotic BCL-xL and BCL-2 proteins to indirectly enhance proapoptotic oligomerization of BAK and BAX [24,25]. We use cookies to help provide and enhance our service and tailor content and ads. The two pathways are independent but connected through BID, and they share caspase-3 as the common effector protease.


The role of p53 in the death or survival of a damaged cell is very complex and is still being investigated, but p53 mutations are found in up to 50% of some cancers. This binding induces oligomerization of the receptor and allows the intracellular extension of the receptor to recruit the corresponding TNF or TRAIL receptor-associated death domain (TRADD) or Fas-associated death domain (FADD) adapter protein that then permits the binding of procaspase-8 to form the death-inducing signaling complex (DISC). Accordingly, as illustrated in Fig. This is accomplished by upregulation of upstream kinases, such as ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3-related), CHK1, and CHK2, which posttranslationally modify p53 at several sites. GAPDH transfection increased apoptosis that was blocked by the GAPDHlysK160R mutant; the former increased PUMA levels but the latter did not; p53 knockdown in the former or the latter decreased apoptosis.


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