Myc down-regulation as a mechanism to activate the Rb pathway in STAT5A-induced senescence.
Senescence is a general antiproliferative program that avoids the expansion of cells bearing oncogenic mutations. We found that constitutively active STAT5A (ca-STAT5A) can induce a p53- and Rb-dependent cellular senescence response. However, ca-STAT5A did not induce p21 and p16(INK4a), which are responsible for inhibiting cyclin-dependent protein kinases and engaging the Rb pathway during the senescence response to oncogenic ras. Intriguingly, ca-STAT5A led to a down-regulation of Myc and Myc targets, including CDK4, a negative regulator of Rb. The down-regulation of Myc was in part proteasome-dependent and correlated with its localization to promyelocytic leukemia bodies, which were found to be highly abundant during STAT5-induced senescence. Introduction of CDK4 or Myc bypassed STAT5A-induced senescence in cells in which p53 was also inactivated. These results uncover a novel mechanism to engage the Rb pathway in oncogene-induced senescence and indicate the existence of oncogene-specific pathways that regulate senescence.
Mallette
Frédérick A
FA
Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Gaumont-Leclerc
Marie-France
MF
Huot
Geneviève
G
Ferbeyre
Gerardo
G
D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000502:physiology*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D046988:Proteasome Endopeptidase Complex