A proline-rich motif in p53 is required for transactivation-independent growth arrest as induced by Gas1.
The involvement of p53 in regulating diverse cellular processes dictates that it must respond to multiple signaling mechanisms, thus coordinating the response to various "stress conditions." Genotoxic stress has served as a paradigm to dissect the transactivation-dependent branch of the pathway by which p53 can induce growth arrest. Alternate mechanisms have been invoked to explain transactivation-independent effects of p53, especially in the context of apoptosis. We have identified a p53-dependent pathway initiated by the gas1 product, a plasma membrane protein highly expressed during G0, which activates a transactivation-independent p53 growth arrest function. Through a detailed deletional analysis and site-specific mutagenesis of p53 we show that the Gas1-dependent signal transduction relies on a proline-rich region (amino acids 63-85) of murine p53. In vivo competition experiments using combinations of such mutants implicate this functional domain of p53 as a docking site in the transmission of antiproliferative signals.
Ruaro
E M
EM
Laboratorio Nazionale Consorzio Interuniversitario per le Biotecnologie, Area Science Park Padriciano 99, 34012 Trieste, Italy.
Collavin
L
L
Del Sal
G
G
Haffner
R
R
Oren
M
M
Levine
A J
AJ
Schneider
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins; D004252:DNA Mutational Analysis; D058851:GPI-Linked Proteins; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011392:Proline; D011485:Protein Binding; D015398:Signal Transduction; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; C501180:Gas1 protein, mouse; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D011392:Proline