TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs

Su, Xiaohua; Chakravarti, Deepavali; Cho, Min Soon; Liu, Lingzhi; Gi, Young Jin; Lin, Yu Li; Leung, Marco L.; El‐Naggar, Adel K.; Creighton, Chad J.; Suraokar, Milind; Wistuba, Ignacio I.; Flores, Elsa R.

doi:10.1038/nature09459

Cited by 384 publications

(442 citation statements)

References 28 publications

(38 reference statements)

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“…Because of the complexity of p63 and the existence of multiple isoforms, TAp63 knockout mice have been generated. Both TAp63 2/2 and TAp63 þ/2 mice develop spontaneous cutaneous SCCs at high frequency that are highly metastatic (Su et al 2010). These findings were further validated in human SCC patient samples in which highgrade, metastatic tumors lose expression of TAp63 and its downstream target genes.…”

Section: P63 In Skin Cancermentioning

confidence: 50%

“…Global effects of p63 on microRNAs are realized via direct regulation and transactivation of the Dicer promoter by TAp63 (Su et al 2010) and the DiGeorge syndrome critical region gene 8 (DGCR8) promoter by DNp63 (Chakravarti et al 2014). In addition, p63 negatively regulates expression of several microRNAs of the miR-34 family, which show reciprocal expression patterns with p63 in the epidermis (Antonini et al 2010).…”

Section: Va Botchkarev and Er Floresmentioning

confidence: 99%

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p53/p63/p73 in the Epidermis in Health and Disease

Botchkarev

Flores

2014

Cold Spring Harbor Perspectives in Medicine

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Although p53 has long been known as the "guardian of the genome" with a role in tumor suppression in many tissues, the discovery of two p53 ancestral genes, p63 and p73, more than a decade ago has triggered a considerable amount of research into the role of these genes in skin development and diseases. In this review, we primarily focus on mechanisms of action of p53 and p63, which are the best-studied p53 family members in the skin. The existence of multiple isoforms and their roles as transcriptional activators and repressors are key to their function in multiple biological processes including the control of skin morphogenesis, regeneration, tumorigenesis, and response to chemotherapy. Last, we provide directions for further research on this family of genes in skin biology and pathology.

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Section: P63 In Skin Cancermentioning

confidence: 50%

Section: Va Botchkarev and Er Floresmentioning

confidence: 99%

p53/p63/p73 in the Epidermis in Health and Disease

Botchkarev

Flores

2014

Cold Spring Harbor Perspectives in Medicine

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“…Together, these results suggest that ⌬Np63 may regulate stem and/or myoepithelial cells through a dominant negative effect on the TAp63, leading to the induction of cell senescence and suppressor functions. 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.…”

Section: Discussionmentioning

confidence: 86%

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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“…Besides that, Suzuki and colleagues (2009) contended that p53 can affect miRNA biogenesis by regulating the process of precursor miRNAs when binding to large DROSHA complex. Supporting findings showed that the mutant p53 binds to inactivate p63, which may reduce the expression of DICER1 and cancer relevant miRNAs (Su et al, 2010). Consequently, the p53 network is a typical example that miRNAs are related to cancerrelevant pathways at multiple stages and are unpredictable.…”

Section: Micrornas As Oncogenes and Tumour Suppressorsmentioning

confidence: 97%

MicroRNAs: Biogenesis, Roles for Carcinogenesis and as Potential Biomarkers for Cancer Diagnosis and Prognosis

Kavitha¹,

Vijayarathna²,

Jothy³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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MicroRNAs (miRNAs) are short non-coding RNAs of 20-24 nucleotides that play important roles in carcinogenesis. Accordingly, miRNAs control numerous cancer-relevant biological events such as cell proliferation, cell cycle control, metabolism and apoptosis. In this review, we summarize the current knowledge and concepts concerning the biogenesis of miRNAs, miRNA roles in cancer and their potential as biomarkers for cancer diagnosis and prognosis including the regulation of key cancer-related pathways, such as cell cycle control and miRNA dysregulation. Moreover, microRNA molecules are already receiving the attention of world researchers as therapeutic targets and agents. Therefore, in-depth knowledge of microRNAs has the potential not only to identify their roles in cancer, but also to exploit them as potential biomarkers for cancer diagnosis and identify therapeutic targets for new drug discovery.

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TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs

Cited by 384 publications

References 28 publications

p53/p63/p73 in the Epidermis in Health and Disease

p53/p63/p73 in the Epidermis in Health and Disease

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

MicroRNAs: Biogenesis, Roles for Carcinogenesis and as Potential Biomarkers for Cancer Diagnosis and Prognosis

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