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Menebar Ilmu Pengetahuan

Crosstalk antar jalur apoptosis

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Death receptors dapat mengaktivasi jalur intrinsik dengan pemotongan anggota superfamili Bcl-2 yaitu protein Bid dimediasi caspase-8. Bid berinteraksi dengan protein pro-apoptosis Bcl-2 yaitu Bax dan Bak, yang menyebabkan pelepasan sitokrom c mitokondria dan Smac/DIABLO yang berikutnya mengaktifkan caspase-9 dan -3. Langkah ini adalah menguatkan induksi apoptosis melalui jalur ekstrinsik.

Sebaliknya, kerusakan DNA dapat menginduksi upregulasi transkripsi beberapa death receptor seperti Fas dan DR5, melalui jalur tergantung atau tidak tergantung p53. Upregulasi ini meningkatkan sensitivitas sel terhadap ligan death receptor. Pada beberapa tipe sel, keterlibatan DR dari jalur ekstrinsik mencukupi komitmen sel untuk apoptosis. Pada beberapa jenis sel lain, komitmen untuk apoptosis memerlukan amplifikasi sinyal DR oleh jalur intrinsik.

Gambar yang lain

In the death receptor (extrinsic) pathway, ligation of death receptors such as death receptor 5 (DR5) or FAS by tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or FAS ligand (FASL) results in receptor trimerization, recruitment of the adaptor molecule FAS-associated death domain protein (FADD) and activation of caspase 8. This can be inhibited by FLICE-like inhibitory protein (FLIP). Active caspase 8 cleaves BH3-interacting domain death agonist (BID) to truncated BID (tBID), which translocates to the mitochondria to trigger the release of second mitochondria-derived activator of caspase (SMAC) and cytochromec. For TNF-stimulated TNF receptor 1 (TNFR1) complexes, the absence of cellular inhibitor of apoptosis (c-IAP) proteins eliminates receptor-interacting protein 1 (RIP1) ubiquitylation. This leads to the association of RIP1 with FADD and caspase 8 to form the pro-apoptotic cytoplasmic complex (complex II) in the cytosol and promote the activation of caspase 8 and subsequently of caspase 3. c-IAP-mediated ubiquitylation of RIP1 blocks the formation of the apoptotic complex, whereas IAP antagonists cause c-IAP degradation thus preventing RIP1 ubiquitylation and allowing apoptosis to proceed. In the mitochondrial pathway, cytochrome c or SMAC are released from the mitochondria into the cytosol. The release of cytochrome c results in the activation of caspase 9 and subsequently of caspase 3, whereas SMAC promotes apoptosis by binding to and antagonizing IAP proteins such as X chromosome-linked IAP (XIAP). Melanoma IAP (ML-IAP) blocks apoptosis by depleting SMAC from XIAP, and IAP antagonists bind ML-IAP to release SMAC blockade. BCL-2 homology 3 (BH3)-only proteins are activated by various insults, which lead to their binding to and inhibition of anti-apoptotic B cell lymphoma 2 (BCL-2) proteins and derepression of the pro-apoptotic proteins BCL-2-associated X protein (BAX) and BCL-2 antagonist/killer 1 (BAK). BCL-XL, B cell lymphoma extra large; MCL1, myeloid cell leukaemia differentiation protein 1; TRADD, TNFR1-associated death domain protein; TRAF2, receptor-associated factor 2.

Berikutnya, jalur apoptosis yang diaktifkan oleh CTL.

Apoptosis can occur via cell-surface-death-receptor- or mitochondrial-dependent pathways. Cytotoxic T lymphocytes (CTLs) express Fas ligand (FasL), which binds to the death receptor Fas on the target cell. Fas then recruits the Fas-associated death domain (FADD) adapter protein to form the death-inducing signalling complex, causing the activation of caspase-8. Caspase-8, in turn, activates the downstream caspases, such as caspase-3, culminating in apoptosis. The death signal can also be initiated by the release of mitochondrial cytochrome c and activation of the apoptotic protease-activating factor 1 (Apaf-1)/caspase-9 complex following internal cellular damage. The released cytochrome c binds to and activates intracellular receptor proteins, such as Apaf-1, which again results in activation of caspases and apoptosis. Many of these interactions found in pro-apoptotic signalling pathways are mediated by one of three related protein–protein interaction motifs: death domains (DDs), death effector domains (DEDs) and caspase-recruitment domains (CARDs). CTLs trigger a second pro-apoptotic pathway through the protease granzyme B, which, once released from CTLs, is translocated into the target cell by perforin. This allows granzyme B to have access to various cytoplasmic substrates and to cleave and activate downstream caspases.

berikutnya

Referensi

Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer. 2002 Jun;2(6):420-30. link

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Author: admin

menebar ilmu pengetahuan

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