|Phospho-RIP (Ser166) (D1L3S) Rabbit mAb 65746||20 µl||
|RIP (D94C12) XP® Rabbit mAb 3493||20 µl||
||H M R Hm Mk||78||Rabbit IgG|
|Phospho-MLKL (Ser358) (D6H3V) Rabbit mAb 91689||20 µl||
|MLKL (D2I6N) Rabbit mAb 14993||20 µl||
|Cleaved Caspase-3 (Asp175) (5A1E) Rabbit mAb 9664||20 µl||
||H M R Mk||17, 19||Rabbit IgG|
|Caspase-3 (D3R6Y) Rabbit mAb 14220||20 µl||
||H M R Mk||35, 19, 17||Rabbit IgG|
|Cleaved Caspase-8 (Asp384) (11G10) Mouse mAb 9748||20 µl||
|Caspase-8 (D35G2) Rabbit mAb 4790||20 µl||
||H M R||10, 57||Rabbit IgG|
|Anti-rabbit IgG, HRP-linked Antibody 7074||100 µl||
|Anti-mouse IgG, HRP-linked Antibody 7076||100 µl||
Monoclonal antibodies are produced by immunizing animals with synthetic peptides surrounding Leu190 of human RIP1, the carboxy terminus of human MLKL and human caspase-8, the amino-terminal sequence of p10 of human caspase-8, amino terminal residues adjacent to Asp175 of human caspase-3, a recombinant protein corresponding to the p20 subunit of caspase-3, and phosphopeptides surrounding human Ser166 of human RIP and Ser358 of human MLKL.
Apoptosis is a regulated physiological process leading to cell death (1,2). Caspases, a family of cysteine acid proteases, are central regulators of apoptosis. Caspases are synthesized as inactive zymogens containing a pro-domain followed by large (p20) and small subunits (p10) that are proteolytically processed in a cascade of caspase activity. Initiator caspases (including 8, 9, 10, and 12) are closely coupled to proapoptotic signals. Once activated, these caspases cleave and activate downstream effector caspases (including 3, 6, and 7), which in turn cleave cytoskeletal and nuclear proteins like PARP, α-fodrin, DFF, and lamin A, and induce apoptosis. Cytochrome c released from mitochondria is coupled to the activation of caspase-9, a key initiator caspase. Apoptosis induced through the extrinsic mechanisms involving death receptors in the tumor necrosis factor receptor superfamily activates caspase-8. Activated caspase-8 cleaves and activates downstream effector caspases, such as caspase-1, -3, -6, and -7. Caspase-3 is a critical executioner of apoptosis, as it is either partially or totally responsible for the proteolytic cleavage of many key proteins, such as the nuclear enzyme poly (ADP-ribose) polymerase (PARP).
Necroptosis, a regulated pathway for necrotic cell death, is triggered by a number of inflammatory signals, including cytokines in the tumor necrosis factor (TNF) family, pathogen sensors such as toll-like receptors (TLRs), and ischemic injury (3,4). Necroptosis is negatively regulated by caspase-8 mediated apoptosis in which the kinase RIP/RIPK1 is cleaved (5). Furthermore, necroptosis is inhibited by a small molecule inhibitor of RIP, necrostatin-1 (Nec-1) (6). Research studies show that necroptosis contributes to a number of pathological conditions, and Nec-1 has been shown to provide neuroprotection in models such as ischemic brain injury (7). RIP is phosphorylated at several sites within the kinase domain that are sensitive to Nec-1, including Ser14, Ser15, Ser161, and Ser166 (8). Phosphorylation drives association with RIP3, which is required for necroptosis (9-11). Mixed lineage kinase domain-like protein (MLKL) is a pseudokinase that was identified as a downstream target of RIP3 in the necroptosis pathway (12). During necroptosis, RIP3 is phosphorylated at Ser227, which recruits MLKL and leads to its phosphorylation at Thr357 and Ser358 (12). Knockdown of MLKL through multiple mechanisms results in inhibition of necroptosis (13). Phosphorylation of MLKL during necroptosis leads to its oligomerization with pore formation that affects membrane integrity (14-17).
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