DNA binding cooperativity of p53 modulates the decision between cell-cycle arrest and apoptosis.
p53 limits the proliferation of precancerous cells by inducing cell-cycle arrest or apoptosis. How the decision between survival and death is made at the level of p53 binding to target promoters remains unclear. Using cancer cell lines, we show that the cooperative nature of DNA binding extends the binding spectrum of p53 to degenerate response elements in proapoptotic genes. Mutational inactivation of cooperativity therefore does not compromise the cell-cycle arrest response but strongly reduces binding of p53 to multiple proapoptotic gene promoters (BAX, PUMA, NOXA, CASP1). Vice versa, engineered mutants with increased cooperativity show enhanced binding to proapoptotic genes, which shifts the cellular response to cell death. Furthermore, the cooperativity of DNA binding determines the extent of apoptosis in response to DNA damage. Because mutations, which impair cooperativity, are genetically linked to cancer susceptibility in patients, DNA binding cooperativity contributes to p53's tumor suppressor activity.
Schlereth
Katharina
K
Department of Hematology, Oncology, and Immunology, Molecular Oncology, Philipps-University, 35032 Marburg, Germany.
Beinoraviciute-Kellner
Rasa
R
Zeitlinger
Marie K
MK
Bretz
Anne C
AC
Sauer
Markus
M
Charles
Joël P
JP
Vogiatzi
Fotini
F
Leich
Ellen
E
Samans
Birgit
B
Eilers
Martin
M
Kisker
Caroline
C
Rosenwald
Andreas
A
Stiewe
Thorsten
T
D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002453:Cell Cycle / Q000235:genetics; D049109:Cell Proliferation; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA