p14ARF (or just ARF) is a human tumor-suppressor gene (the mouse homolog is p19ARF); it is activated by E2F-1 and stabilizes p53. Abnormal proliferation (due to defect of Rb, expression of oncogenes such as Ras, E1A, or Myc) results in deregulated E2F-1 activity, which induces p14ARF and stabilizes p53. This would lead to cell-cycle arrest or apoptosis unless a second lesion occurred such as mutation in p14ARF or p53 itself.
p16INK4a is a tumor-suppressor which inhibits the cyclin-dependent kinases 4 and 6. Its inhibitory effect results from its binding to CDk4/6 and by this preventing the formation of the Cdk4/6-cyclin D complex. INK4 inhibitors (p16INK4a and the related p19INK4a) also distort the Cdk4/6 kinase catalytic cleft and interfere with its ATP binding.
p21 WAF1/CIP1 encodes a 21 kDa protein that inhibits the kinase activity of the cdk2-cyclin complex required for transition from G1 to S phase in the cell cycle. p21 was simultaneously identified as WAF1 (Wild-type p53-Activated Fragment1) and as CIP1 (Cyclin-dependent kinase Inhibitor Protein), suggesting a direct link between p53, negative regulation of the kinases required for G1-S transition and therefore G1 arrest.
Caspase-inhibitor from insect Baculovirus; inhibits ICE family members with broader specificity than CrmA: it inhibits Caspase-1 and caspase-3 equally well. More...
p53 is a tumor-suppressor gene which codes for a transcriptionally active protein involved in cell cycle arrest, DNA repair and apoptosis. Approximately 50% of all major forms of cancer contain p53 missense mutations, and p53 knockout mice are highly susceptible to spontaneous tumor formation. p53 is induced by DNA damage or stress (heat shock, viral infection) and results in G1 cell cycle arrest or apoptosis. Several response genes (p21, mdm-2, GADD45, bax ...) have been identified that are transcriptionally activated by p53, but p53 also can repress transcription of genes with promoters lacking p53-binding sites (e.g. hsp70, c-fos, c-jun, Rb, bcl-2 ...). In apoptosis, p53 may also have transcription-independent functions. More...
p73 is a homologue of p53; p73 can induce cell cycle arrest and apoptosis. It also transcriptionally induces the expression of some (but not all) known p53 target genes such as p21.
The PAAD domain was named after the protein families from which it was discovered: Pyrin, Aim (absent-in-melanoma), Asc, and death-domain (DD)-like. PAAD can be found in proteins involved in apoptosis, inflammation, cancer and immune responses. Its location within these proteins and predicted fold suggests that it functions as a protein-protein interaction domain, possibly uniting different signaling pathways (Pawlowski et al., 2001, Trends Biol. Sc., 26(2): 85-87).
PAG608 encodes a nuclear zinc-finger protein, preferentially localizing to nucleoli. PAG608 is a target gene of p53 and can promote apoptosis upon transient overexpression.
A form of programmed cell death without prominent chromatin condensation and mainly characterized by cytoplasmic vacuolization (Leist and Jaattela, 2001, Nat. Rev. Mol. Cell Biol., 2: 589-98).
Poly(ADP-Ribose) Polymerase; PARP is a nuclear enzyme that upon DNA damage catalyses the poly(ADP-ribosyl)ation (PARation) of nuclear proteins such as p53, histones, topoisomerases I and II, SV40T antigen, DNA polymerase alpha, PCNA, and it also automodifies itself. PARP is activated following DNA strand breakage during DNA repair and is essential for the maintenance of genomic integrity and for survival in response to genotoxic insults. PARP was reported to modify p53 early during apoptosis and by this possibly stabilizing p53. At later stages PARP is cleaved (= inactivated) by caspase-3 and PAR is removed from p53, concomitant with the onset of the execution phase of apoptosis (Simbulan-Rosenthal et al., 1999, Cancer Res., 59: 2190-94). PARP-/- fibroblasts did not show PARation and no signs of apoptosis after anti-Fas treatment, suggesting an essential role for PARP and PARation in the early (induction) stages of apoptosis (Simbulan-Rosenthal et al., 1998, JBC, 273: 13703-13712).
Caspase-dependent proteolysis of PARP-1 results in the formation of a 24 kDa DNA binding domain (DBD) and a 89 kDa catalytic fragment. The 24 kDa fragment has been shown to inactivate the enzymatic activity of PARP-1 in a dominant-negative manner. Inactivation of PARP during the execution phase of apoptosis by caspase cleavage might be necessary to prevent NAD+ and ATP depletion and thus to prevent a switch from an ATP-dependent apoptotic mode of cell death to an energy depletion-induced necrotic mode (Amours et al, 2001, J. Cell Science, 114(20) 3771-77).
Peripheral Blood Lymphocyte.
Programmed Cell Death: the term programmed cell death is usually reserved for physiological conditions during which disposal of cells takes place, such as development and morphogenesis, clonal selection of lymphocytes, and cell renewal in epithelia. On the contrary, the term apoptosis indicates a form of active cell death triggered by pathological conditions such as inflammation, cancer, viral infections, or exposure to a wide variety of chemical and physical stimuli.
p53-induced gene 3 (PIG3) was one of altogether 14 PIGs which were identified by SAGE to be upregulated upon overexpression of p53. PIG3 was found to be markedly induced in response to oxidative stress.
The PML gene was first identified as being translocated (and fused with the retinoic acid receptor alpha, RAR-alpha) in acute promyelocytic leukaemia (APL). PML encodes a cell growth and tumor suppressor which was reported to be a mediator of multiple apoptotic signals, including Fas, TNF-alpha, and interferons type I and II. PML was reported to be required for caspase-1 and -3 activation upon exposure to these stimuli (Zhu-Gang et al, 1998, Nature Genetics, 20: 266-271). PML also might be involved in the expression of genes required for the formation of functional MHC class I receptors: malfunction of PML thus may affect the susceptibility of tumor cells to be recognized by T cells, what may allow tumors to escape the immune system (Zheng et al., 1998, Nature, 396: 373-376).
ProMyelocytic Leukaemia Nuclear Bodies (PML_NBs), also called PODs or ND10 bodies or Kr bodies, are macromolecular multiprotein complexes that are present in all cultured cell lines as well as in vivo. Immunofluorescence studies have demonstrated that PODs can vary in number and size depending on cell type, hormonal exposure, and cell cycle. A major component of the POD is the PML protein, which was originally identified as the fusion partner of RARa in the chromsomal translocation t(15;17). The expression of the PML-RARalpha fusion protein disrupts the structural integrity of PODs and may contribute to the oncogenic state in APL patients. Besides PML, other constituents of PODs are CBP , p53, and HIPK2 and all those factors are involved in transcriptional control either in transcriptional activation or repression (Doucas, 2000, Biochem Pharm., 60: 1197-1201).
PODs PML Oncogenic Domains (PODs), see PML-NBs.
The major clinical manifestations of Prader-Willi syndrome (PWS) are distinct from those of AS and include small hands and feet, hypogonadism, variable mental retardation, and a marked obesity resulting from hyperphagia. In contrast to Angelman Syndrome, PWS results from a lack of a normal paternal contribution to chromosome 15q11-q13, with most cases resulting from de novo deletion of this chromosomal subregion or from maternal uniparental disomy of chromosome 15.
The 26S proteasome is a large (2MDa) ATP-dependent proteolytic complex that is found in the cytosol and in the nucleus of all eukaryotic cells, and it has emerged to be the key enzyme responsible for nonlysosomal protein degradation. The 26S proteasome complex, which constitutes up to 1% of the total protein in mammalian cells, consists of two asymetric 19S caps flanking a barrel-shaped core of about 700 kDa, the 20S proteasome. The caps contain approximately 15 different subunits, six of those are ATPases serving to unfold the substrate before it is translocated into the inner cavities of the core enzyme. Other subunits of the cap complex are implicated in the recognition of substrate proteins carrying degradation signals and thus conferring selctivity upon degradation by the proteasome. The covalent attachment of ubiquitin to a target protein is seen as the principal mechanism by which proteins are marked for degradation by the proteasome. The molecular architecture of the 20S proteasome is highly conserved from archaebacteria to higher eukaryotes. Most prokaryotic proteasomes are built from two subunits, alpha and beta, whereas eukaryotiv proteasomes typically contain 14 different, but related, subunits which can be classified as alpha-type and beta-type subunits according to sequence similarity (Baumeister and Lupas, Curr. Opin. Struc. Biol., 1997, 7:273-78). There is increasing line of evidence that protein degradation by the proteasome is involved in the regulation of many important biological processes within the cell, such as cell cycle, transcription, endocytosis, and apoptosis, see proteasome and apoptosis.
Proteasome and Apoptosis
Several different modes of protein degradation have been described, but the degradation of short-lived regulatory proteins is thought to be mediated by ubiquitin-proteasome-dependent pathways. Many different substrates have been identified to be ubiquitinated and subsequently degraded by the proteasome, and it is actually not surprising that the ubiquitin-proteasome-dependent system has been implicated in various important biological processes, such as cell cycle progression, immune response, transcriptional regulation, endocytosis but also apoptosis (Vu and Sakamoto, 2000, Mol Gen. Metab., 71:261-266). Execution of cell death needs to be kept under stringent control, and indeed, the ubiquitin-proteasome-dependent pathways appear to play a major role in regulating the stability and and activity of several factors involved in apoptosis, including the Bcl-2 family of proteins, the IAPs, p53, IkB, as well as IKK (Jesenberger and Jentsch, 2002, Nat. Mol. Cell Biol., 3:112). Another link between the ubiquitin/proteasome pathways and apoptosis is provided by the observation that treatment of cell lines with proteasome inhibitors usually results in apoptosis induction, although in some cell types proteasome inhibitors appear to protect those cells to apoptosis induced by various factors (Orlowski, 1999, Cell Death Diff., 6: 303-313). Recently, proteasome inhibitors have been introduced into clinical studies investigating their potential capability to enhance the effect of chemotherapeutical drugs towards otherwise resistant tumor cells (Adams et al., 2000, Inv. New Drugs, 18: 109-121). Studying the multiple roles of the ubiquitin-proteasome system in the regulation of apoptosis will give more insight into the complex signalling networks involved but also might lead to novel therapeutic approaches for some human diseases that are linked with dysregulated apoptosis, such as neurodegenerative diseases (Alzheimer, Parkinson, ALS, Huntington's Disease), autoimmune diseases, and cancer.
Proteasome inhibitors are currently evaluated as new chemotherapeutic agents in cancer patients with advanced disease. By inhibiting the proteasome they influence cell cycle regulation, angiogenesis and apoptosis, what might explain their potential anti-tumor activity. Almost all of the inhibitors described to date (tripeptide aldehydes, boronic acid peptide inhibitors, and natural compounds such as lactacystin, eponomycin, cyclosporine A, rapamycin) are predominantly potent inhibitors of the chymotryptic activity of the proteasome what appears to be sufficient to block proteolysis of ubiquitinated proteins (besides chymotryptic activity, the proteasome also possesses tryptic and peptidylglutamyl catalytic activity).
In the presence of proteasome inhibitors, many otherwise short-lived proteins are stabilized, especially cell cycle related protein substrates such as the cyclin dependent kinase inhibitors (p21, and p27) resulting in cell cycle arrest. Other proteins involved in cell cycle regulation are stabilized in the presence of proteasome inhibitors, i.e. cyclins (A,B,D,E), p53, IkB-alpha, p130, E2F-1, cdc25 and more.
14-3-3 proteins are a family of proteins that recognize and bind to phosphoserine in specific contexts (Muslin et al., 1996, Cell, 84: 889-97). 14-3-3 proteins, e.g. bind to the C-terminus of the serine 376-dephosphorylated p53, and by this possibly activate its DNA binding ability and transcriptional activity. 14-3-3 proteins also bind to phosphorylated Bad and prevent it from inhibiting Bcl-2. Transcription of the 14-3-3 proteins 14-3-3-sigma and RAD3 is activated by p53 following DNA damage. RAD3 results in the inactivation of cdc25 and thus G2 arrest, whereas 14-3-3-sigma is important for maintaining G2 arrest by sequestering phosphorylated Cdc2-cyclin B1 from the nucleus into the cytosol (Chan et al., 1999, Nature, 401:616-20).
Permeability Transition More... .
Permeability Transition pore; supposedly involved in the loss of the mitochondrial transmembrane potential and the release of cytochrome c into the cytosol. The PT pore includes VDAC, ANT and cyclophilin D.
PTEN is a tumor suppressor gene that codes for a phosphatase; it dephosphorylates phosphatidylinosyol-3,4,5-trisphosphate (PIP3) to PIP2. Thus PTEN activity cont