Inhibition of apoptosis by MAD1 is mediated by repression of the PTEN tumor suppressor gene.
The MYC/MAX/MAD network of transcriptional regulators controls distinct aspects of cell physiology, including cell proliferation and apoptosis. Within the network MAD proteins antagonize the functions of MYC oncoproteins, and the latter are deregulated in the majority of human cancers. While MYC sensitizes cells to proapoptotic signals, the transcriptional repressor MAD1 inhibits apoptosis in response to a broad range of stimuli, including oncoproteins. The molecular targets of MAD1 that mediate inhibition of apoptosis are not known. Here we describe the phosphatase and tensin homologue deleted on chromosome ten (PTEN) tumor suppressor gene as a target of MAD1. By binding to the proximal promoter region, MAD1 downregulated PTEN expression. PTEN functions as a lipid phosphatase that regulates the phosphatidylinositol 3-kinase/AKT pathway. Indeed MAD1-dependent repression of PTEN led to activation of AKT and subsequent stimulation of the antiapoptotic NF-kappaB pathway. Interfering with AKT function affected the control of Fas-induced apoptosis by MAD1. In addition, knockdown of PTEN using small interfering RNA (siRNA) or the lack of PTEN rendered cells insensitive to inhibition of apoptosis by MAD1. These findings identify the PTEN gene as a target of the MYC-antagonist MAD1 and provide a molecular framework critical for the ability of MAD1 to inhibit apoptosis.
Rottmann
Sabine
S
Abteilung Biochemie und Molekularbiologie, Institut für Biochemie, Universitätsklinikum, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Speckgens
Stefanie
S
Lüscher-Firzlaff
Juliane
J
Lüscher
Bernhard
B
D000818:Animals; D017209:Apoptosis; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D045744:Cell Line, Tumor; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C079439:MXD1 protein, human; D012097:Repressor Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse