BRCA1 185delAG mutant protein, BRAt, up-regulates maspin in ovarian epithelial cells

O'Donnell, Joshua D.; Linger, Rebecca J.; Kruk, Patricia A.

doi:10.1016/j.ygyno.2009.10.052

Cited by 10 publications

(19 citation statements)

References 20 publications

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“…There are several possibilities that can explain the apparent lack of c-Fos binding, including Jun binding to another Fos family member or the AP-1 site on the Maspin promoter having a higher affinity for Jun homodimers than Jun/Fos heterodimers. Nevertheless, inhibition of c-Jun alone has been found to inhibit Maspin promoter activity (39). Mutational analyses for each AP-1 and Ets-1 sites in PAR-1-silenced cell lines further revealed that the proximal AP-1 and Ets-1 sites were essential for regulation of Maspin promoter activity.…”

Section: Discussionmentioning

confidence: 99%

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

Villares

Zigler

Dobroff

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The thrombin receptor protease activated receptor-1 (PAR-1) is overexpressed in metastatic melanoma cell lines and tumor specimens. Previously, we demonstrated a significant reduction in tumor growth and experimental lung metastasis after PAR-1 silencing via systemic delivery of siRNA encapsulated into nanoliposomes. Gene expression profiling identified a 40-fold increase in expression of Maspin in PAR-1-silenced metastatic melanoma cell lines. Maspin promoter activity was significantly increased after PAR-1 silencing, suggesting that PAR1 negatively regulates Maspin at the transcriptional level. ChIP analyses revealed that PAR-1 decreases binding of Ets-1 and c-Jun transcription factors to the Maspin promoter, both known to activate Maspin transcription. PAR-1 silencing did not affect Ets-1 or c-Jun expression; rather it resulted in increased expression of the chromatin remodeling complex CBP/p300, as well as decreased activity of the CBP/p300 inhibitor p38, resulting in increased binding of Ets-1 and c-Jun to the Maspin promoter and higher Maspin expression. Functionally, Maspin expression reduced the invasive capability of melanoma cells after PAR-1 silencing, which was abrogated after rescuing with PAR-1. Furthermore, tumor growth and experimental lung metastasis was significantly decreased after expressing Maspin in a metastatic melanoma cell line. Moreover, silencing Maspin in PAR-1-silenced cells reverted the inhibition of tumor growth and experimental lung metastasis. Herein, we demonstrate a mechanism by which PAR-1 negatively regulates the expression of the Maspin tumor-suppressor gene in the acquisition of the metastatic melanoma phenotype, thus attributing an alternative function to PAR-1 other than coagulation. melanoma progression | transcriptional regulation | G protein-coupled receptor signaling | Serpin B5

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Section: Discussionmentioning

confidence: 99%

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

Villares

Zigler

Dobroff

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The BRCA1 185delAG mRNA is predicted to produce a short, approximately 5-kDa peptide (E23fsX17). Although this peptide has not been detected endogenously, exogenous overexpression of a BRCA1 peptide consisting of aa 1-23fsX17 was reported to induce phenotypes not associated with full-length BRCA1, including enhanced IL-1β expression, and to promote apoptosis (45,46). However, endogenously generated small peptide products normally located in the structured RING region of the protein may not be folded and are likely to be degraded.…”

Section: Methodsmentioning

confidence: 99%

RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance

Wang¹,

Krais²,

Bernhardy³

et al. 2016

Journal of Clinical Investigation

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“…It inhibits cellular motility, invasiveness and angiogenesis, and provides sensitivity to apoptosis in tumor cells [20], [21]. Maspin expression predicts a better prognosis in different types of cancers: breast [22], [23], prostate [24], [25], colon [26], oral squamous cell carcinoma [27], lung [28], larynx [29], malignant melanoma [30] and ovarian cancer [31], although recently it has been reported that it might act as tumor promoter in colorectal or pancreatic cancers [32], [33]. Maspin also acts as a suppressor of metastasis in different types of cancer such as prostate, liver and breast [17], [34].…”

Section: Introductionmentioning

confidence: 99%

Increased IKKα Expression in the Basal Layer of the Epidermis of Transgenic Mice Enhances the Malignant Potential of Skin Tumors

et al. 2011

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Non-melanoma skin cancer is the most frequent type of cancer in humans. In this study we demonstrate that elevated IKKα expression in murine epidermis increases the malignancy potential of skin tumors. We describe the generation of transgenic mice overexpressing IKKα in the basal, proliferative layer of the epidermis and in the outer root sheath of hair follicles. The epidermis of K5-IKKα transgenic animals shows several alterations such as hyperproliferation, mislocalized expression of integrin-α6 and downregulation of the tumor suppressor maspin. Treatment of the back skin of mice with the mitogenic agent 12-O-tetradecanoylphorbol-13-acetate causes in transgenic mice the appearance of different preneoplastic changes such as epidermal atypia with loss of cell polarity and altered epidermal tissue architecture, while in wild type littermates this treatment only leads to the development of benign epidermal hyperplasia. Moreover, in skin carcinogenesis assays, transgenic mice carrying active Ha-ras (K5-IKKα-Tg.AC mice) develop invasive tumors, instead of the benign papillomas arising in wild type-Tg-AC mice also bearing an active Ha-ras. Therefore we provide evidence for a tumor promoter role of IKKα in skin cancer, similarly to what occurs in other neoplasias, including hepatocarcinomas and breast, prostate and colorectal cancer. The altered expression of cyclin D1, maspin and integrin-α6 in skin of transgenic mice provides, at least in part, the molecular bases for the increased malignant potential found in the K5-IKKα skin tumors.

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BRCA1 185delAG mutant protein, BRAt, up-regulates maspin in ovarian epithelial cells

Cited by 10 publications

References 20 publications

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance

Increased IKKα Expression in the Basal Layer of the Epidermis of Transgenic Mice Enhances the Malignant Potential of Skin Tumors

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