p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor

Jung, Mun-Su; Yun, Jeanho; Chae, Hee-Don; Kim, Jeongmin; Kim, Sun-Chang; Choi, Tae-Saeng; Shin, Deug Y.

doi:10.1038/sj.onc.1204748

Cited by 88 publications

(61 citation statements)

References 54 publications

(59 reference statements)

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“…22,27,52 In our study, salivary carcinomas with a high TAp63 isoform manifested a biologically indolent behavior compared with those with a high ⌬N isoform. 44,46,53,54 Our findings are in agreement with studies of tumor models in which a tumor suppressor role for the TA isoform in tumorigenesis has been attributed to its effect on senescence. Therefore, we contend that overexpression of the ⌬N isoform leads to enhanced cell migration and proliferation directly by an oncogenic effect and indirectly by regulating the TA to block cell senescence.…”

Section: Discussionsupporting

confidence: 81%

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Mitani

Weber

et al. 2011

The American Journal of Pathology

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The TP63 gene, a TP53 homologue, encodes for two main isoforms by different promoters: one retains (TA) and the other lacks (⌬N) the transactivation domain. p63 plays a critical role in the maintenance of basal and myoepithelial cells in ectodermally derived tissues and is implicated in tumorigenesis of several neoplastic entities. However, the biological and regulatory roles of these isoforms in salivary gland tumorigenesis remain unknown. Our results show a reciprocal expression between TA and ⌬N isoforms in both benign and malignant salivary tumors. The most dominantly expressed were the ⌬N isoforms, whereas the TA isoforms showed generally low levels of expression, except in a few tumors. High ⌬Np63 expression characterized tumors with aggressive behavior, whereas tumors with high TAp63 expression were significantly smaller and less aggressive. In salivary gland cells, high expression of ⌬Np63 led to enhanced cell migration and invasion and suppression of cell senescence independent of TAp63 and/or TP53 gene status. We conclude the following: i) overexpression of ⌬Np63 contributes to salivary tumorigenesis, ii) ⌬Np63 plays a dominant negative effect on the TA isoform in the modulation of cell migration and invasion, and iii) the ⌬N isoform plays an oncogenic role and may represent an attractive target for therapeutic intervention in patients with salivary carcinomas.

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Section: Discussionsupporting

confidence: 81%

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Mitani

Weber

et al. 2011

The American Journal of Pathology

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“…NF-Y was bound on the Cdc25B promoter in uninduced cells but was absent in p53-induced cells. This result suggests that p53 downregulates Cdc25B by reducing the binding of NF-Y on the Cdc25B promoter, thus preventing the full activation of this promoter, as has already been shown for cyclinB and cdk1 (Jung et al, 2001). To demonstrate that NF-Y is involved in p53 regulation of Cdc25B, we inhibited NF-YB expression, one of the three subunits of the NF-Y factor, by transfecting HCT116 cells with NF-YB siRNA.…”

Section: Resultsmentioning

confidence: 63%

Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors

et al. 2011

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Cdc25B phosphatases function as key players in G2/M cell cycle progression by activating the CDK1-cyclinB1 complexes. They also have an essential role in recovery from the G2/M checkpoint activated in response to DNA damage. Overexpression of Cdc25B results in bypass of the G2/M checkpoint and illegitimate entry into mitosis, and also causes replicative stress, leading to genomic instability. Thus, fine-tuning of Cdc25B expression level is critical for correct cell cycle progression and G2 checkpoint recovery. However, the transcriptional regulation of Cdc25B remains largely unknown. Earlier studies have shown that the tumor suppressor p53 overexpression transcriptionally represses Cdc25B; however, the molecular mechanism of this repression has not yet been elucidated, although it was suggested to occur through the induction of p21. Here we show that Cdc25B is downregulated by the basal level of p53 in multiple cell types. This downregulation also occurs in p21À/À cell lines, indicating that p21 is not required for p53-mediated regulation of Cdc25B. Deletion and mutation analyses of the Cdc25B promoter revealed that downregulation by p53 is dependent on the presence of functional Sp1/Sp3 and NF-Y binding sites. Furthermore, chromatin immunoprecipitation analyses show that p53 binds to the Cdc25B promoter and mediates transcriptional attenuation through the Sp1 and NF-Y transcription factors. Our results suggest that the inability to downregulate Cdc25B after loss of p53 might contribute to tumorigenesis.

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“…p63 can induce expression of molecules such as CD95 and TRAIL which influence apoptosis, [25][26][27][28] or inhibit proliferation by blocking binding of the NF-Y transcription factor which is required for transcription of cyclin B and cdk1 genes involved in regulating the cell cycle. 29 Determination of the functional significance of p63 in giant cell tumor of bone requires further study.…”

Section: Discussionmentioning

confidence: 99%

Giant cell tumor of bone express p63

Dickson

Wunder

et al. 2008

Modern Pathology

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p63 contributes to skeletal development and tumor formation; however, little is known regarding its activity in the context of bone and soft tissue neoplasms. The purpose of this study was to investigate p63 expression in giant cell tumor of bone and to determine whether it can be used to discriminate between other giant cell-rich tumors. Seventeen cases of giant cell tumor of bone were examined to determine the cell type expressing p63 and identify the isoforms present. Total RNA or cell protein was extracted from mononuclear-or giant cellenriched fractions or intact giant cell tumor of bone and examined by RT-PCR or western blot, respectively. Immunohistochemistry was used to evaluate p63 expression in paraffin embedded sections of giant cell tumor of bone and in tumors containing multinucleated giant cells, including: giant cell tumor of tendon sheath, pigmented villonodular synovitis, aneurysmal bone cyst, chondroblastoma, and central giant cell granuloma. The mononuclear cell component in all cases of giant cell tumor of bone was found to express all forms of TAp63 (a, b, and c), whereas only low levels of the TAp63 a and b isoforms were detected in multinucleated cells; DNp63 was not detected in these tumors. Western blot analysis identified p63 protein as being predominately localized to mononuclear cells compared to giant cells. This was confirmed by immunohistochemical staining of paraffin-embedded tumor sections, with expression identified in all cases of giant cell tumor of bone. Only a proportion of cases of aneurysmal bone cyst and chondroblastoma showed p63 immunoreactivity whereas it was not detected in central giant cell granuloma, giant cell tumor of tendon sheath, or pigmented villonodular synovitis. The differential expression of p63 in giant cell tumor of bone and central giant cell granuloma suggest that these two tumors may have a different pathogenesis. Moreover, p63 may be a useful biomarker to differentiate giant cell tumor of bone from central giant cell granuloma and other giant cell-rich tumors, such as giant cell tumor of tendon sheath and pigmented villonodular synovitis.

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p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor

Cited by 88 publications

References 54 publications

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Expression and Regulation of the ΔN and TAp63 Isoforms in Salivary Gland Tumorigenesis

Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors

Giant cell tumor of bone express p63

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