Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

Roth, Judith; Koch, Philipp; Contente, Ana; Dobbelstein, Matthias

doi:10.1016/s0016-5085(00)84796-4

Cited by 14 publications

(18 citation statements)

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“…These findings suggest that the p53 status of the BCP-1 line (S262/S262) limits p53 transcriptional capabilities. The observation that BCBL-1 cells robustly induce all p53 target genes is consistent with the previously reported phenotype of the M246I mutation (56) and indicates that BCBL-1 cells may have developed apoptotic resistance through additional mutations. Together, these findings show that p53 signaling is fully functional in PEL, engaging multiple pathways to mediate the therapeutic effects of Nutlin-3 and DNA-damaging agents.…”

Section: )supporting

confidence: 90%

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Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy

Petre

Sin

Dittmer

2007

J Virol

108

114

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The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is associated with Kaposi's sarcoma (KS) as well as primary effusion lymphomas (PEL). The expression of viral proteins capable of inactivating the p53 tumor suppressor protein has been implicated in KSHV oncogenesis. However, DNA-damaging drugs such as doxorubicin are clinically efficacious against PEL and KS, suggesting that p53 signaling remains intact despite the presence of KSHV. To investigate the functionality of p53 in PEL, we examined the response of a large number of PEL cell lines to doxorubicin. Two out of seven (29%) PEL cell lines harbored a mutant p53 allele (BCBL-1 and BCP-1) which led to doxorubicin resistance. In contrast, all other PEL containing wild-type p53 showed DNA damage-induced cell cycle arrest, p53 phosphorylation, and p53 target gene activation. These data imply that p53-mediated DNA damage signaling was intact. Supporting this finding, chemical inhibition of p53 signaling in PEL led to doxorubicin resistance, and chemical activation of p53 by the Hdm2 antagonist Nutlin-3 led to unimpaired induction of p53 target genes as well as growth inhibition and apoptosis.

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Section: )supporting

confidence: 90%

“…The M246I mutation (BCBL-1) was initially identified in the H23 lung cancer cell line and was reported to maintain DNA binding to consensus p53 binding elements (56). However, transactivation of nonconsensus elements by p53 M246I was limited, resulting in decreased apoptotic induction.…”

Section: Vol 81 2007mentioning

confidence: 99%

Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy

Petre

Sin

Dittmer

2007

J Virol

108

114

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“…17 Indeed, in A549 and H460 cells that have wild-type p53, RIP1 knockdown elevated the protein expression of p53 together with its targets p21 and MDM2 (Figure 1d and Supplementary Figure 1c). With RIP1 stable knockdown, p21 induction was also seen in H23 cells with a p53 mutation (M246I) capable of activating p21 expression, 18 but p21 induction was not observed in p53 inactive mutant (R273L) H2009 and p53 null H1299 cells (Supplementary Figure 1c). Transient knockdown of p53 with siRNA in RIP1-deficient cells attenuated p21 expression (Figure 1e and Supplementary Figure 1d).…”

Section: Resultsmentioning

confidence: 99%

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

Chen

Wang²,

Bai

et al. 2014

Cell Death Differ

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Aerobic glycolysis or the Warburg effect contributes to cancer cell proliferation; however, how this glucose metabolism pathway is precisely regulated remains elusive. Here we show that receptor-interacting protein 1 (RIP1), a cell death and survival signaling factor, regulates mitochondrial oxidative phosphorylation and aerobic glycolysis. Loss of RIP1 in lung cancer cells suppressed peroxisome proliferator-activated receptor c coactivator-1a (PGC-1a) expression, impairing mitochondrial oxidative phosphorylation and accelerating glycolysis, resulting in spontaneous DNA damage and p53-mediated cell proliferation inhibition. Thus, although aerobic glycolysis within a certain range favors cancer cell proliferation, excessive glycolysis causes cytostasis. Our data suggest that maintenance of glycolysis by RIP1 is pivotal to cancer cell energy homeostasis and DNA integrity and may be exploited for use in anticancer therapy. A cell's metabolism is optimized for its function and adapts to environmental changes; therefore, it is pivotal to differentiation, proliferation, survival and death. In the presence of ample oxygen, cancer cells prefer glycolysis over mitochondrial respiration for energy supply, which is known as the Warburg effect or aerobic glycolysis.1,2 Although aerobic glycolysis was originally thought to complement impaired mitochondrial respiration, recent investigations suggest that it is a driving force in cancer cell transformation and proliferation. 3,4 In coordination with the tricarboxylic acid cycle and mitochondrial respiration, cancer cells increase glycolysis to support their rapid proliferation. This 'metabolic transformation' in cancer cells not only meets their energy requirements but also provides the building blocks for synthesis of biomass and for maintenance of redox homeostasis. 5,6 Thus, the metabolic transformation is believed to offer cancer cells a selective growth advantage compared with their normal counterparts and to contribute to drug resistance. Many oncogenes such as c-Myc and Akt, and tumor suppressors such as p53 are involved in the regulation of glycolysis and mitochondrial metabolism, serving as evidence of the necessity for metabolic adaptation in cancer cells. 7,8 However, how metabolic transformation is precisely regulated needs further elucidation.Receptor-interacting protein 1 (RIP1) is a serine/threonine kinase with functions in cell proliferation, survival and death.9-11 The role of RIP1 in cell survival is achieved mainly through its function as an adaptor in signal pathways, such as NF-kB and PI3K/Akt, that suppress apoptosis. The kinase activity of RIP1 is involved in programmed necrosis or necroptosis.12 Although RIP1 can translocate to the mitochondria in certain circumstances and can modulate ADP/ ATP exchange and the production of mitochondrial reactive oxygen species (ROS), [13][14][15][16] whether RIP1 regulates cell energy homeostasis is unknown.In an attempt to investigate the role of RIP1 in cell proliferation, we uncovered a function for this protein in...

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“…As a conformational change in the core has a major impact on binding to p73 (Strano et al, 2000;Gaiddon et al, 2001;Bensaad et al, 2003), these results suggest that the Pro/Arg residue at position 72 can affect the folding of the core. Yet another study has supported a role of the Pro-rich domain (residues 62-93) in core domain folding: deletion of this region resulted in attenuation of DNA binding similar to the effect produced by certain tumor-derived point mutations in the core (Roth et al, 2000). In addition, a synthetic peptide spanning the Pro-rich region was shown to affect the DNAbinding properties of the core domain (Mu¨ller-Tiemann et al, 1998).…”

Section: Structural Basis For Mutant P53 Reactivationmentioning

confidence: 94%

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

2007

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Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

Cited by 14 publications

References 0 publications

Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy

Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy

RIP1 maintains DNA integrity and cell proliferation by regulating PGC-1α-mediated mitochondrial oxidative phosphorylation and glycolysis

Reactivation of mutant p53: molecular mechanisms and therapeutic potential

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