The polyproline region of p53 is required to activate apoptosis but not growth arrest

Sakamuro, Daitoku; Sabbatini, Peter; White, Eileen; Prendergast, George C.

doi:10.1038/sj.onc.1201263

Cited by 303 publications

(289 citation statements)

References 43 publications

(66 reference statements)

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“…The N-terminal region contains also a proline rich region (amino acid 63 ± 97) with striking similarity to SH3-binding proteins and which is required for p53-mediated apoptosis in some experimental systems (Sakamuro et al, 1997), for suppressing tumour cell growth (Walker and and for human papilloma E6 to target degradation (Li and Co no, 1996). The fact that this region is proline-rich and contains ®ve repeats of the SH3 binding motif PXXP suggests that it may be involved in physical interaction with elements of signal transduction pathways, for example c-abl.…”

Section: Amino-terminal Region Of P53mentioning

confidence: 99%

Twenty years of p53 research: structural and functional aspects of the p53 protein

1999

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Section: Amino-terminal Region Of P53mentioning

confidence: 99%

Twenty years of p53 research: structural and functional aspects of the p53 protein

1999

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“…The vmyc mediated apoptotic pathways appear to be dependent on the tumor suppressor p53 since coexpression of v-Myc and wild type p53 in the v-Myctransformed cells promotes apoptosis (Wang et al, 1993a). However, over-expression of Bcl-2 can protect v-Myc-transformed cells from apoptosis (Wang et al, 1993b), an observation that is consistent with the role of c-Myc in apoptosis and its relationship with p53 and Bcl-2 (Bissonnette et al, 1992;Evan et al, 1992;Hermeking and Eick, 1994;Sakamuro et al, 1995;Wagner et al, 1994). These results suggest that during the process of transformation, secondary events occur in v-myc expressing cells that lead to the inactivation of the apoptotic function of v-Myc.…”

Section: Mechanisms Of Transformation and Tumor Progressionmentioning

confidence: 77%

The v-myc oncogene

Lee

Reddy

1999

Oncogene

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“…Bax) or anti-apoptotic genes (e.g. Bcl-2) and there is no indication that the p53-independent cmyc pathway (Sakamuro et al, 1995;Hermeking et al, 1995;Friedlander et al, 1996) is central for ME-cell apoptosis (Figure 7). Although an elevated protein kinase A (PKA) activity and higher AP-1 levels (Marti et al, 1994), as well as a transition from anti-apoptotic Bcl-xL to the apoptotic Bcl-xS alternative splice form were observed one day after lactation (Heermeier et al, 1996), no signi®cant di erence was demonstrable in this regard between the T/t antigen positive and negative ME-cells.…”

Section: Sv40 T/t-antigen and Me Cell Apoptosismentioning

confidence: 99%

SV40 T/t-antigen induces premature mammary gland involution by apoptosis and selects for p53 missense mutation in mammary tumors

et al. 1998

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We recently established transgenic animals (WAP-SV-T/ t) carrying the early coding region of Simian Virus 40 (SV40) under the transcriptional control of the whey acidic milk protein promoter (WAP), which restricts the expression of the transgene to mammary gland epithelial cells (ME-cells). SV40 T/t-antigen synthesis causes premature mammary gland involution during late pregnancy by inducing apoptosis and leads to development of mammary tumors after the ®rst lactation period in both p53 positive (WAP-SV-T/t) and p53 negative double transgenic animals (WAP-SV-T/t.p537/7). The high apoptotic rate persists in all of the T/t-antigen positive breast tumor cells, as well as in established MEtissue culture cell lines. ME-cells which spontaneously switch o the expression of the WAP-SV-T/t transgene do not undergo apoptosis. However, these cells again exhibit an extensive DNA fragmentation when SV40 T/ t-antigen synthesis is reintroduced, which indicates that it is the expression of T/t antigen which is the critical factor for induction of apoptosis. In addition, we isolated several ME-cell lines from di erent breast tumors which have spontaneously lost the T/t-antigen yet remain maximally transformed. Strikingly, these cells contain a missense mutation of the p53 gene at codon 242 (p53 242 ), which substitutes alanine for glycine. This mutation increases p53 stability and it reduces the transactivating function of p53, albeit without a ecting the ability of the protein to interact with the DNA. This indicates that p53 missense mutations are selected for in breast tumors initially expressing T/t-antigen. Therefore, the p53 242 mutation is su cient to maintain the transformed state after the ME-cells have switched o the WAP-SV-T/t transgene. Interestingly, the p53 minus state per se is not su cient to induce ME-cell transformation since homozygous null mice for the p53 gene (p537/7) fail to develop breast cancer.

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The polyproline region of p53 is required to activate apoptosis but not growth arrest

Cited by 303 publications

References 43 publications

Twenty years of p53 research: structural and functional aspects of the p53 protein

Twenty years of p53 research: structural and functional aspects of the p53 protein

The v-myc oncogene

SV40 T/t-antigen induces premature mammary gland involution by apoptosis and selects for p53 missense mutation in mammary tumors

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