In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 4964-4964
Abstract:
p53 is one of the major tumor suppressors and promotes apoptotic cell death by transcriptional activation of pro-apoptotic target genes. In malignant human tumors, however, its tumor suppressive activity is frequently inactivated by somatic mutation and/or chromosomal deletion. To enhance the efficacy of chemotherapeutic agents in p53-deficient tumors, it is necessary to elucidate the p53-independent mechanisms of apoptotic cell death. Recently, we have shown that TATA-binding protein-like protein (TLP) transactivates one of p53 family members, TAp63, and induces apoptosis in a p53-independent manner. In response to DNA damage by etoposide, TLP is induced to translocate from cytoplasm to nucleus and enhance promoter activity of TAp63 through direct recruitment onto the promoter. TAp63 stimulated by TLP promotes apoptotic cell death in Hep3B cells null for the p53 alleles. The expression levels of TLP mRNA in human primary non-small lung cancers is low compared with corresponding normal tissues and the downregulation is significantly correlated with low levels of TAp63 and poor outcome of patients’ survival. These results suggest the potential for TLP-TAp63 pro-apoptotic pathway as a therapeutic target for malignant lung cancers. In this study, we analyzed expression of p53 family genes in 106 primary neuroblastomas using quantitative real time RT-PCR, and found that the levels of only TAp63 expression was significantly high in favorable neuroblastomas as compared with unfavorable tumors (p=0.00696) and that its expression was inversely correlated with MYCN expression (p=0.0350). MYCN oncogene is frequently amplified and overexpressed in unfavorable neuroblastoma, and in vitro studies have demonstrated that downregulation of MYCN is the critical steps for neuronal cell death induced by retinoic acids (RA) regardless of p53 status in tumors. However, the precise molecular mechanisms of the down-regulation of MYCN by RA have not been elusive. Intriguingly, TLP and TAp63 are induced in response to RA treatment and TAp63 directly represses MYCN transcription. In addition, RA treatment also inhibits positive auto-regulation of MYCN, leading to further down-regulation of MYCN mRNA levels. Collectively, our results suggest that TAp63 is highly expressed in favorable neuroblastomas and contributes to repression of MYCN by RA treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4964.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-4964
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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