A novel role for p73 in the regulation of Akt-Foxo1a-Bim signaling and apoptosis induced by the plant lectin, Concanavalin A.
Virtually all human cancers encounter disruption of the "p53 network." From a therapeutic point of view, it is important to devise strategies that eliminate cancer cells, which are often defective in functional p53 and protect p53-expressing normal cells. By comparing the response of a pair of isogenic cell lines, we identify a plant-derived compound, Concanavalin A (Con A), which differentially kills p53-null cells. Further, we find that p53 family member, p73, plays a critical role that is unmasked in the absence of p53. Con A treatment leads to induction of p73 and several others that are important mediators of apoptosis and act downstream, such as p21, Bax, Foxo1a, and Bim. Inactivation of p73 reverses the expression of these proteins and apoptosis. Inhibition of Akt activation sensitizes otherwise resistant cells. These observations thus reveal a novel role for p73 in the regulation of Akt-Foxo1a-Bim signaling and apoptosis especially when p53 is absent.
Amin
A R M Ruhul
AR
Department of Genetics and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Paul
Rajib K
RK
Thakur
Vijay S
VS
Agarwal
Munna L
ML
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D037121:Plant Lectins / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009687:Nuclear Proteins; D037121:Plant Lectins; D011518:Proto-Oncogene Proteins; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D003208:Concanavalin A; D051057:Proto-Oncogene Proteins c-akt