PKCepsilon induces Bcl-2 by activating CREB.
Protein kinase C epsilon (PKCepsilon) is a transforming oncogene and an important anti-apoptotic protein. We previously demonstrated that overexpression of PKCepsilon in MCF-7 breast cancer cells caused an increase in anti-apoptotic Bcl-2 and a decrease in pro-apoptotic Bid, attenuating tumor necrosis factor-alpha (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. The objective of our present study was to determine the mode of induction of Bcl-2 by PKCepsilon in breast cancer cells. siRNA silencing of either PKCepsilon or Akt in MCF-7 cells, which overexpress Akt, decreased Bcl-2 protein and mRNA levels. However, knockdown of PKCepsilon, but not Akt, led to the decrease in Bcl-2 at both protein and mRNA levels in MDA-MB-231 breast cancer cells, which overexpress PKCepsilon but contain little constitutively-active Akt. Knockdown of PKCepsilon decreased phosphorylation of cAMP response element-binding protein (CREB) at Ser133 in MDA-MB-231 cells, and depletion of CREB by siRNA decreased Bcl-2 at both the protein and mRNA levels. In addition, knockdown of CREB sensitized MDA-MB-231 cells to TRAIL-mediated cell death. These results suggest that PKCepsilon regulates Bcl-2 induction through activation of the transcription factor CREB.
Shankar
Eswar
E
Department of Molecular Biology and Immunology, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA.
Krishnamurthy
Soumya
S
Paranandi
Rajiv
R
Basu
Alakananda
A
D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D051057:Proto-Oncogene Proteins c-akt; C497255:PRKCE protein, human; D051744:Protein Kinase C-epsilon