Regulation of the p53-MDM2 pathway by 14-3-3 sigma and other proteins.
The 14-3-3 sigma (sigma) protein, a unique member of 14-3-3 family, is a negative regulator of the cell cycle and is induced by p53 to initiate cell cycle checkpoint control after DNA damage. Among the 14-3-3 family members, 14-3-3 sigma is uniquely induced by p53 and has a positive feedback effect on p53 activity in response to DNA damage. Although 14-3-3 sigma is linked to p53-regulated cell cycle checkpoint control, the detailed mechanisms of cell cycle regulation by 14-3-3 sigma remain unclear. Decreased expression of 14-3-3 sigma was reported in several types of carcinomas, suggesting that the negative regulatory role of 14-3-3 sigma in the cell cycle is compromised during tumorigenesis. Given the fact that p53's tumor suppressive function is lost in almost half of all human cancers and that 14-3-3 sigma's activity is linked to the p53 network, a perspective regarding the p53/14-3-3 sigma relationship is needed for cancer research. Here we discuss the mechanisms by which 14-3-3 sigma-stabilizes p53 with the hope that these insights may be applied to develop targeted therapeutic strategies for cancer treatment.
Lee
Mong-Hong
MH
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, USA. mhlee@mdanderson.org
Lozano
Guillermina
G
D048948:14-3-3 Proteins; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D005092:Exonucleases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005095:Exoribonucleases; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D000076183:Tripartite Motif-Containing Protein 28; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D043222:Ubiquitin Thiolesterase; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D000076084:Ubiquitin-Specific Peptidase 7
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C403591:PSMD10 protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C111164:BRAP protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D010450:Endopeptidases; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7; D046988:Proteasome Endopeptidase Complex