The p53 Tumor Suppressor Gene: Structure, Function and Mechanism of Action

Choisy-Rossi, Caroline; Reisdorf, Philippe; Yonish-Rouach, Elisheva

doi:10.1007/978-3-540-69184-6_8

Cited by 13 publications

(21 citation statements)

References 195 publications

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“…To assess the functional importance of these two mutations, we compared the two amino acid residues within 20 TP53 protein sequences from rat down to fish and found that these two residues are conserved during evolution (Choisy-Rossi, et al, 1999). Replacement of these conserved amino acids in the DNA binding domain of TP53 may interfere with the binding ability of TP53 to its target genes (Cho, et al, 1994).…”

Section: Intron3 Exon4mentioning

confidence: 99%

Unique substitution ofCHEK2 andTP53 mutations implicated in primary prostate tumors and cancer cell lines

et al. 2006

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Genetic defects in CHEK2 and TP53 have been implicated in prostate cancer development. However, the interaction of these two genes in prostate cancer tumorigenesis has not been investigated. We previously described 11 CHEK2 mutations in a group of 84 primary prostate tumors. In this report, we screened the same group of tumors for TP53 mutations and revealed nine somatic and two germline mutations. One germline TP53 mutation (c.408A>T/p.Gln136His) and two somatic mutations (c.1022T>G/p.Phe341Cys and c.108-109ins22/p.His37fsX13) are novel to human cancer. More interestingly, CHEK2 and TP53 mutations were observed to be mutually substituted in these tumors. Analysis of five commonly used prostate cancer cell lines revealed that four cell lines harboring TP53 mutations carry no CHEK2 mutation while the only cell line (LNCaP) carrying wild-type TP53 harbors a CHEK2 mutation. The novel CHEK2 mutation (c.1160C>T/p.Thr387Asn) identified in LNCaP cells changes amino acid Thr387 to Asn which has been shown to impair CHEK2 autophosphorylation and activation. Our data suggest that the CHEK2 and TP53 mutations can substitute each other in at least 25% (21/84) of prostate cancers and that DNA damage-signaling pathway plays an important role in prostate cancer tumorigenesis. Published

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Section: Intron3 Exon4mentioning

confidence: 99%

Unique substitution ofCHEK2 andTP53 mutations implicated in primary prostate tumors and cancer cell lines

et al. 2006

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“…The human p53 gene lies on chromosome 17p and encodes a nuclear, DNA-binding phosphoprotein of 393 amino acid residues (3,4). P53 consists of several protein domains including an N-terminal transactivation domain (amino acid residues 1-42); a central sequencespecific DNA-binding domain (amino acid residues 90-295); and C-terminal domains for tetramerization (amino acid residues 323-355; p53 functions in cells as a tetramer), nuclear localization (amino acid residues 316-325) and negative regulatory control (amino acid residues 80-93 and 368-393) (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…The N-terminal transactivation domain contains many acidic residues and one of the five highly evolutionarily conserved sequences in p53 (amino acid residues 12-20) which is required for its transcriptional activation function (3,4). The N-terminal domain also contains binding sites for several other cellular and viral proteins (TBP, hTAFII31, hTAFII70, p62, RP-A, CBP/p300, mdm-2, E1B55, E6 and Hbx) (3,4). Some of these, such as the cellular protein mdm-2 and the adenoviral protein E1B55, can inhibit the transcriptional activation function of p53 (3,4).…”

Section: Introductionmentioning

confidence: 99%

“…The N-terminal domain also contains binding sites for several other cellular and viral proteins (TBP, hTAFII31, hTAFII70, p62, RP-A, CBP/p300, mdm-2, E1B55, E6 and Hbx) (3,4). Some of these, such as the cellular protein mdm-2 and the adenoviral protein E1B55, can inhibit the transcriptional activation function of p53 (3,4). Mdm-2 binding is also known to promote ubiquination and rapid degradation of p53, probably an important normal control mechanism for regulating the level and hence activity of p53 in cells (3,4).…”

Section: Introductionmentioning

confidence: 99%

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Computational protein chemistry of p53 and p53 peptides

et al. 2004

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Computational protein chemistry has potential to contribute to the development of new therapeutic approaches in medicine in several different ways, including indirectly by increasing understanding of the disease-associated changes in protein structure that are mechanistically important, which can have diagnostic implications, as well as directly in designing peptides to counteract the patho-physiologic effects of these changes. Studies of the role of the tumor suppressor protein p53 in the carcinogenic process provide examples of both types of contribution. Computational studies of the effects of mutations in p53 on its structure have provided insights into cancer mechanisms and have served to elucidate potential new diagnostic approaches based on the identification of changes in p53 structure. Computational studies of p53 peptides have contributed to identifying and optimizing the structural characteristics that contribute to their activity in selectively killing cancer cells.

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“…Белок регулирует многие клеточные функции, включая митотический цикл, репарацию поврежденной ДНК, дифференцировку кле-ток и их гибель по типу апоптоза [5]. Базальный уровень белка в большинстве нормально функционирующих кле-ток крайне низок, концентрация его резко повышается при воздействии различных стрессорных факторов, что приводит к подавлению процессов клеточного деления путем индукции транскрипции генов р21 WAFI/CIPI , bax, GADD45 и hdm2 [9]. Элиминация р53 тесно связана с про-теином MDM2, являясь одновременно продуктом данного белка; MDM2 обеспечивает его расщепление в протеасо-мах 26S путем образования комплекса р53-mdM2 и бло-кирование основных его функций [10].…”

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