Warning: Undefined variable $zfal in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 525
Deprecated: str_replace(): Passing null to parameter #3 ($subject) of type array|string is deprecated in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 525
Warning: Undefined variable $sterm in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 530
free
Warning: Undefined variable $sterm in C:\Inetpub\vhosts\kidney.de\httpdocs\mlpefetch.php on line 531
free free
English Wikipedia
Nephropedia Template TP (
Twit Text
DeepDyve Pubget Overpricing |
lüll Caspase-, cathepsin-, and PERK-dependent regulation of MDA-7/IL-24-induced cell killing in primary human glioma cells Yacoub A; Park MA; Gupta P; Rahmani M; Zhang G; Hamed H; Hanna D; Sarkar D; Lebedeva IV; Emdad L; Sauane M; Vozhilla N; Spiegel S; Koumenis C; Graf M; Curiel DT; Grant S; Fisher PB; Dent PMol Cancer Ther 2008[Feb]; 7 (2): 297-313Melanoma differentiation-associated gene-7/interleukin-24 (mda-7/IL-24) is a novel cytokine displaying selective apoptosis-inducing activity in transformed cells without harming normal cells. The present studies focused on defining the mechanism(s) by which a GST-MDA-7 fusion protein inhibits cell survival of primary human glioma cells in vitro. GST-MDA-7 killed glioma cells with diverse genetic characteristics that correlated with inactivation of ERK1/2 and activation of JNK1-3. Activation of JNK1-3 was dependent on protein kinase R-like endoplasmic reticulum kinase (PERK), and GST-MDA-7 lethality was suppressed in PERK-/- cells. JNK1-3 signaling activated BAX, whereas inhibition of JNK1-3, deletion of BAX, or expression of dominant-negative caspase-9 suppressed lethality. GST-MDA-7 also promoted a PERK-, JNK-, and cathepsin B-dependent cleavage of BID; loss of BID function promoted survival. GST-MDA-7 suppressed BAD and BIM phosphorylation and heat shock protein 70 (HSP70) expression. GST-MDA-7 caused PERK-dependent vacuolization of LC3-expressing endosomes whose formation was suppressed by incubation with 3-methyladenine, expression of HSP70 or BiP/GRP78, or knockdown of ATG5 or Beclin-1 expression but not by inhibition of the JNK1-3 pathway. Knockdown of ATG5 or Beclin-1 expression or overexpression of HSP70 reduced GST-MDA-7 lethality. Our data show that GST-MDA-7 induces an endoplasmic reticulum stress response that is causal in the activation of multiple proapoptotic pathways, which converge on the mitochondrion and highlight the complexity of signaling pathways altered by mda-7/IL-24 in glioma cells that ultimately culminate in decreased tumor cell survival.|Apoptosis Regulatory Proteins/genetics[MESH]|Apoptosis/*drug effects/genetics[MESH]|Autophagy-Related Protein 5[MESH]|Beclin-1[MESH]|Caspases/*physiology[MESH]|Cathepsins/*physiology[MESH]|Cell Culture Techniques[MESH]|Cell Death/drug effects[MESH]|Cell Survival/genetics[MESH]|Endoplasmic Reticulum Chaperone BiP[MESH]|Endoplasmic Reticulum/metabolism[MESH]|Glioma/enzymology/genetics/*pathology[MESH]|Glutathione Transferase/genetics[MESH]|Green Fluorescent Proteins/genetics/metabolism[MESH]|Humans[MESH]|Interleukins/genetics/*physiology[MESH]|Membrane Proteins/genetics[MESH]|Microtubule-Associated Proteins/genetics/metabolism[MESH]|Models, Biological[MESH]|Recombinant Fusion Proteins/genetics[MESH]|Signal Transduction/genetics[MESH]|Transfection[MESH]|Tumor Cells, Cultured[MESH]|eIF-2 Kinase/genetics/*physiology[MESH] |