Allosteric activation of latent p53 tetramers

Hupp, Ted R.; Lane, David P.

doi:10.1016/s0960-9822(00)00195-0

Cited by 277 publications

(229 citation statements)

References 45 publications

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“…The last 30 residues of the C-terminal domain were proposed to negatively regulate DNA binding by an allosteric mechanism. This hypothesis was based on the observation that the interaction of p53 with a short oligonucleotide containing a consensus p53-binding site is greatly enhanced either by the deletion of the C-terminal basic region (30 residues) or by binding of the antibody PAb421 to the same region (Hupp and Lane, 1994). This was confirmed by a study showing that p53 transcriptional activity is activated by PAb421 in cells (Lu and Lane, 1993).…”

Section: Structural Basis For Mutant P53 Reactivationmentioning

confidence: 95%

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

2007

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Section: Structural Basis For Mutant P53 Reactivationmentioning

confidence: 95%

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

2007

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“…In this basic domain, serine 392 in human (389 in mouse) is phosphorylated only by exposure to ultraviolet (UV) but not g-irradiation (IR) (Kapoor and Lozano, 1998;Lu et al, 1998). Phosphorylation of this serine results in stabilizing the p53 tetramer and enhancing sequencespecific DNA-binding ability of p53 in vitro (Hupp and Lane, 1994;Sakaguchi et al, 1997). Other studies also support the importance of phosphorylation at this serine in cell-cycle arrest and apoptosis functions of p53 (Milne et al, 1992;Hao et al, 1996;Achison and Hupp, 2003).…”

Section: Analyses Of Es Cells and Mefs Reveal No Effects Onmentioning

confidence: 97%

“…Genotoxic or oncogenic stresses stabilize p53 through post-translational modifications such as phosphorylation. Phosphorylation at the aminoterminus disrupts interaction with Mdm2 and phosphorylation at the carboxyl terminus increases oligomerization (Hupp and Lane, 1994;Sakaguchi et al, 1997;Shieh et al, 1997;Chehab et al, 1999;Craig et al, 1999;Unger et al, 1999a). Lysines at the carboxyl terminus are also modified by ubiquitination, acetylation, neddylation, sumoylation and methylation (Gu and Roeder, 1997;Gostissa et al, 1999;Rodriguez et al, 1999Rodriguez et al, , 2000Chuikov et al, 2004;Harper, 2004;Xirodimas et al, 2004;Friedler et al, 2005).…”

Section: A P53 Mutant Lacking Transcriptional Activity That Also Cannmentioning

confidence: 99%

Crippling p53 activities via knock-in mutations in mouse models

Iwakuma

Lozano

2007

Oncogene

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The tumor suppressor p53 is the most frequently mutated gene in human cancer. In vivo models have been generated using knock-in alleles in which missense mutations are introduced that mimic the kinds of mutations found in human cancers, or that abolish specific p53 functions. Critically, these studies examine the in vivo and physiological functions of p53. Studies indicate that p53 missense mutations in the DNA-binding domain identical with those inherited in the Li-Fraumeni syndrome, have distinct properties. Studies in mice with mutants that separate cell-cycle arrest and apoptosis functions of p53 show delayed onset of tumor development, suggesting that both p53 functions are crucial for suppressing tumors. Mice with mutations at post-translational modification sites exhibit subtle effects on p53 activity and tumor development, indicating a fine-tuning mechanism of p53 activity in vivo. Importantly, each mutant mouse has a distinct phenotype, suggesting diverse and exquisite mechanisms of p53 regulation in different environments, different tissues and different genetic backgrounds. The generation of these mutant p53 knock-in mice has laid the groundwork for future studies to elucidate the in vivo physiological function of mutant p53 and to examine cooperating effects in combination with other alterations.

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“…As shown in Figure 3b, when compared to the maximal LDH release (MLR), early LDH release into the cytoplasm by 1 hr did not occur after exposure to 30 M p53p-Ant. The positive control for necrosis, 30 M p53(15)Ant that is a p53 N-terminal peptide (aa [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] shown by us to induce only necrosis without any evidence for apoptosis, 36,37 was carried out simultaneously. The N-terminal p53 peptide induced significant necrosis as evidenced by an early LDH release assay by 1 hr.…”

Section: P53 C-terminal Peptide-induced Cell Death: Apoptosis Vs Necmentioning

confidence: 99%

“…24 The sequence-specific DNA-binding activity of p53 seems to be regulated negatively by its C-terminal 30 aa segment (aa 363-393) and by a N-terminal proline-rich motif located between aa 80 -93. 25,26 Synthetic peptides corresponding to the C-terminal domain of p53, aa residues 363-393, bind directly in vitro to wild-type (wt) p53. Binding studies with p53 proteins that contain selected deletions suggest that binding of the p53 peptide aa 363-393 to p53 protein requires the presence of both C-terminal aa 363-393 and N-terminal aa 80 -93 sequences in the p53 protein.…”

mentioning

confidence: 99%

Selective induction of apoptosis through the FADD/caspase‐8 pathway by a p53 c‐terminal peptide in human pre‐malignant and malignant cells

Mao

Rosal

et al. 2005

Intl Journal of Cancer

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A p53 C-terminal peptide (aa 361-382, p53p), fused at its Cterminus to the minimal carrier peptide of antennapedia (17 aa, Ant; p53p-Ant), induced rapid apoptosis in human cancer cells, via activation of the Fas pathway. We examined p53p-Ant mechanism of action, toxicity in various human normal, non-malignant, pre-malignant and malignant cancer cells and investigated its biophysical characteristics. p53p-Ant selectively induced cell death in only pre-malignant or malignant cells in a p53-dependent manner and was not toxic to normal and non-malignant cells. p53p-Ant was more toxic to the mutant p53 than wild-type p53 phenotype in H1299 lung cancer cells stably expressing human temperature-sensitive p53 mutant 143Ala. Surface plasmon resonance (BIACORE) analysis demonstrated that this peptide had higher binding affinity to mutant p53 as compared to wild-type p53. p53p-Ant induced-cell death had the classical morphological characteristics of apoptosis and had no features of necrosis. The The p53 tumor suppressor gene is one of the most commonly mutated genes found in human malignancies. 1 More than 50% of human tumors, including breast cancers, are associated with missense mutations or deletions of p53 and most of the missense mutations map to the DNA-binding domain of the protein. 2,3 p53 protein functions in the transcription of growth inhibiting genes, apoptosis, cell cycle arrest and DNA repair. 4 -6 p53 is a sequencespecific transcription factor that transactivates a number of genes whose products are involved in cell growth regulation. These include p21 (a cyclin-dependent kinase inhibitor known to arrest the cell cycle mainly in G1/S phase), GADD45 for DNA repair and Bax and Fas/APO-1 for apoptosis. 7-11 p53 induced Fas-FADD binding and transiently sensitized cells to Fas-induced apoptosis. 12 Programmed cell death depends on conserved structural moieties that transmit and regulate the death signal. This is most evident in death receptors of the tumor necrosis factor receptor (TNF-R) super-family. The intracellular regions of the Fas/CD95 and TNFR1 death receptors have a moderately well conserved NH2-region of about 80 residues that is required for death signalling and has been called the 'death domain' (DD). 13,14 Fas/CD95 induces rapid apoptosis upon binding to Fas ligand through the autocrine/paracrine signalling pathway. 15 When activated, the intracellular death domain in Fas/CD95 binds to FADD/MORT-1 at its C-terminus, which then recruits caspase-8 to FADD. A member of the TNF ligand family identified more recently is TNF-related apoptosis-inducing ligand (TRAIL). TRAIL shows high homology to Fas Ligand and binds to the TRAIL receptor family. TRAILinduced caspase activation shares many of same caspases involved in Fas/CD95 and TNF-induced cell death mechanisms. 16 FADD/ MORT-1 is a cytosolic adaptor protein, which is critical for signalling from Fas/APO-1 and other TNF-R family members. 17 Two protein interaction domains have been identified in FADD/ MORT-1. The C-terminal 'death domain' is needed for ...

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Allosteric activation of latent p53 tetramers

Cited by 277 publications

References 45 publications

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

Crippling p53 activities via knock-in mutations in mouse models

Selective induction of apoptosis through the FADD/caspase‐8 pathway by a p53 c‐terminal peptide in human pre‐malignant and malignant cells

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