Grail as a molecular determinant for the functions of the tumor suppressor p53 in tumorigenesis.
The transcription factor p53 is a multifunctional tumor suppressor that arrests the cell cycle in response to stress and modulates the DNA repair process or induces apoptosis. The cellular level and activity of p53 are tightly controlled to maintain proper functioning. This study identified a novel p53-binding glycoprotein, gene related to anergy in lymphocytes (Grail), which formed a negative feedback loop (similar to that of Mdm2). Grail physically and functionally interacted with the N-terminus of p53 to target its degradation and modulate its transactivation activity. Grail also senses and regulates cellular p53 levels, modulates a panel of p53-targeted promoters, and has a role in p53-induced apoptosis in cultured cells. Overexpression of Grail inhibited p53-induced apoptosis by increasing p53 degradation. However, cells not expressing Grail failed to undergo p53-dependent apoptosis, resulting in p21-dependent G1 arrest. Thus, Grail may provide a novel regulatory route for controlling p53 activity under stress conditions.
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Y-C
YC
Chen
J Y-H
JY
Chan
Y-L
YL
Chiu
S-T
ST
Liu
G
G
Lozano
S-L
SL
Wang
C-L
CL
Ho
S-M
SM
Huang
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases