APOPTOSIS

Activation of Apoptosis by TSP-1 in Microvascular Endothelial Cell As tissues grow they require angiogenesis to occur if they are to be supplied with blood vessels and survive.  Factors that inhibit angiogenesis might act as cancer therapeutics by blocking vessel formation in tumors and starving cancer cells. AKT Signaling Pathway Many cell-surface receptors induce production of second messengers like PIP3, phosphatidylinositol 3,4,5-trisphosphate, that convey signals to the cytoplasm from the cell surface.  Caspase Signaling Pathway Apoptosis, programmed cell death, is triggered by a variety of stimuli, including cell surface receptors like FAS, mitochondrial response to stress, and cytotoxic T cells. Caspases are a class of cysteine proteases that includes several representatives involved in apoptosis. The caspases convey the apoptotic signal in a proteolytic cascade, with caspases cleaving and activating other caspases that then degrade other cellular targets that lead to cell death. cd40 Signaling Pathway CD40, also known as Tumor Necrosis Factor Receptor Super Family member 5, binds CD40 Ligand leading to the phosphorylation of the inhibitors of NFkappaB and ultimately transcription mediated by NFkappaB. The CD40 glycoprotein is found as a 45-48 kD Type I integral membrane protein on B-cells in the peripheral blood and tonsils but is not found on terminally differentiated B-cells. Chemical Damage Induced Signaling Pathway D4GDI Signaling Pathway D4-GDI (GDP dissociation inhibitor) is a negative regulator of the ras related Rho Family of GTPases. Since the rho GTPases promote cytoskeletal and membrane changes associated with apoptotic cell death, the removal of the D4-GDI block through its cleavage is important for inducing apoptosis. Caspase-3 cleaves the 28 kDa mature form of D4-GDI to give a 5 kDa and 23 kDa Size fragment. The 23 kDa fragment then translocates to the nucleus. The mechanisms involving cleavage of D4-GDI with apoptosis are not presently known. Activation of the Jun N-Terminal kinase, a regulator of apoptosis, may be one of the mechanisms. FAS signaling pathway Receptors in the TNF receptor family are associated with the induction of apoptosis, as well as inflammatory signaling. The Fas receptor (CD95) mediates apoptotic signaling by Fas-ligand expressed on the surface of other cells. Induction of apoptosis through DR3 and DR4/5 Death Receptors Apoptosis is specifically induced via signaling through a family of receptors known collectively as 'death receptors' including Fas, TNFR, DR3, -4 and -5. Death receptor ligands characteristically initiate signaling via receptor oligomerization, recruitment of specialized adaptor proteins and activation of caspase cascades. OX40 Signaling Pathway OX40 (CD134) is also known as Tumor Necrosis Factor Receptor Super Family member 5. p53 Signaling Pathway p53 is a transcription factor who's activity is regulated by phosphorylation. The function is p53 is to keep the cell from progressing through the cell cycle if there is damage to DNA present. It may do this in multiple ways from holding the cell at a checkpoint until repairs can be made to causing the cell to enter apoptosis if the damage cannot be repaired. The critical role of p53 is evidenced by the fact that it is mutated in a very large fraction of tumors from nearly all sources. Proteasome Complex Attachment of the ubiquitin peptide to proteins targets them for proteolytic degradation by a complex cellular structure, the proteasome. The regulated proteolysis of proteins by proteasomes removes denatured, damaged or improperly translated proteins from cells and regulates the level of proteins like cyclins or some transcription factors. PTEN dependent cell cycle arrest and apoptosis PTEN is a tumor suppressor gene. Recombinant PTEN is capable of dephosphorylate phosphatidylinositol 3,4,5-triphosphate[PI(3,4,5)P3], the product of phosphatidylinositol 3 -kinase. Many of the cancer-related mutations have been mapped to the phosphatase catalytic domain, it has been suggested that the phosphatase activity of PTEN is required for its tumor suppressor function.  SODD/TNFR1 Signaling Pathway TNFR1 Signaling Pathway TNFR1 (a.k.a. p55, CD120a) is the receptor for TNF(alpha) and also will bind TNF(beta). Upon binding TNF(alpha) a TNFR1+ cell is triggered to undergo apoptosis. This critical regulatory process is accomplished by activating the proteolytic caspase cascade that results in the degradation of many critical cellular proteins. TNFR2 Signaling Pathway TNFR2 is the receptor for the 171 amino acid 19 kD TNF(beta) (a.k.a. lymphotoxin). TNF(beta) is produced by activated lymphocytes and can be cytotoxic to many tumor and other cells. In neutrophils, endothelial cells and osteoclasts TNF(beta) can lead to activation while in many other cell types it can lead to increased expression of MHC and adhesion molecules. Toll-like Receptor Pathway

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