Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li–Fraumeni syndrome

Srivastava, Shiv; Zou, Zhiqiang; Pirollo, Kathleen F.; Blattner, William A.; Chang, Esther H.

doi:10.1038/348747a0

Cited by 1,099 publications

(516 citation statements)

References 23 publications

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“…63,64 p53 mutations are common in RMS with nearly 50% of cases exhibiting a lesion in the p53 gene. 63,65 p53 mutations are not as common in ES with frequencies of 3-16%; 31,66 however, the subset of ES patients with mutant p53 have a markedly poorer outcome. 30 The frequency of p53 mutations in undifferentiated STS in children is unknown.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

et al. 2004

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Sarcomas, or tumors of connective tissue, represent roughly 20% of childhood cancers. Although the cure rate for sarcomas in general has significantly improved in the last 10 years, there continue to be subgroups that are difficult to treat. High-grade or metastatic soft-tissue sarcomas and rhabdomyosarcomas (RMS) of the extremities remain therapeutic challenges and their prognosis is often poor. The future of sarcoma therapy will likely include molecular approaches including gene/protein expression profiling and gene-based therapy. Most sarcomas harbor defects in the p53 or pRb pathways. The tumor suppressor p53 is central to regulation of cell growth and tumor suppression and restoring wild-type p53 function in pediatric sarcomas may be of therapeutic benefit. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. Studies of this approach, however, remain limited in pediatric cancers, including sarcomas. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (C135S) and lacZ, we studied the effect of adenoviralmediated gene therapy in four pediatric sarcoma cell lines, RD and Rh4 (RMS), Rh1 (Ewing's sarcoma) and A204 (undifferentiated sarcoma). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. Cells treated with Ad-wtp53 show upregulation of the p53 downstream targets, p21 CIP1/WAF1 and bax. Growth curves demonstrate suppression of cell growth over a period of 4 days and cells treated with Ad-wtp53 demonstrate a significant increase in sensitivity to the chemotherapeutic agents, cisplatin and doxorubicin. Our results indicate that restoration of wild-type p53 function in pediatric sarcoma cells could provide a basis for novel approaches to treatment of this disease.

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Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

et al. 2004

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“…98,99 Furthermore, a rare genetic disorder, Li-Fraumeni syndrome results from the inheritance of a single mutated copy of the p53 gene. 100,101 These patients are characterised by a high incidence of early onset of various cancers, particularly lymphoma, leukaemia and several forms of sarcoma, which develop following the somatic loss of the remaining wild-type p53 allele in cancerinitiating cells.…”

Section: Mcl1mentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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“…The frequent lesions of the p53 gene in a wide range of human cancers (Greenblatt et al, 1994), as well as the predisposition of individuals bearing germinal p53 mutation to develop malignancies (Malkin et al, 1990;Srivastava et al, 1990), suggest that the loss of a normal p53 activity contributes to tumorigenesis. In Friend tumor cells, p53 allelic deletions or missense mutations suggest an incidence of wild-type p53 extinction in the immortalization of erythroid progenitor cells.…”

Section: Introductionmentioning

confidence: 99%

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation

et al. 1998

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Spi-1 transcriptional activation and wild-type p53 extinction are two oncogenic alterations involved in the malignant transformation of erythroblasts during the Friend acute erythroleukemia. To dissect the contribution of these alterations in the deregulation of the di erentiation and proliferation of erythroblasts, we generated spi-1 transgenic mice. Analysis of these animals revealed that Spi-1 overexpression was directly involved in the block of proerythroblast di erentiation. However, the erythroleukemia that develops in these animals evolved in two steps. During the early step (HS1 step), non tumorigenic proerythroblasts remained strictly dependent upon erythropoietin (Epo) for their survival and proliferation. Later on, Epo-independent and tumorigenic proerythroblasts emerged (HS2 step) suggesting that other oncogenes cooperate with Spi-1 to lead to a fully malignant phenotype. By provirus tagging, we demonstrate that the HS1 step was clonal indicating that a cell selection must occur in vivo. Analysis of the nature of p53 in both the in vivo HS1 and HS2 proerythroblasts and in cultured erythroblastic cell lines showed that ± p53 was normal in the HS1 primary tissues but was mutated in the HS1 cultured cell lines ± p53 was frequently altered in HS2 primary tissues but was found normal in some mice. These data indicate that (i) the blockage of the erythroblast di erentiation by Spi-1 occurs independently of p53 alteration (ii) p53 alteration is not necessary to confer Epo independence and tumorigenicity to spi-1 transgenic proerythroblasts.

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Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li–Fraumeni syndrome

Cited by 1,099 publications

References 23 publications

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

The BCL-2 protein family, BH3-mimetics and cancer therapy

Spi-1 transgenic mice develop a clonal erythroleukemia which does not depend on p53 mutation

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