PDX-1 and the Pancreas

Ashizawa, Satoshi; Brunicardi, F Charles; Wang, Xiaoping

doi:10.1097/00006676-200403000-00001

Cited by 92 publications

(76 citation statements)

References 110 publications

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“…Pancreatic ducts were examined for signs of islet neogenesis in young and old mice by staining for insulin and transcription factor pancreatic duodenal homeobox 1 (PDX-1), both postnatal markers of b-cells (Ashizawa et al 2004). In 3-week-old PTTGK/K mice, insulin and (PDX-1) immunoreactive cells lining pancreatic ducts were detected ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Murine pituitary tumor-transforming gene functions as a securin protein in insulin-secreting cells

Yu¹,

Cruz²,

Calzi³

et al. 2006

Journal of Endocrinology

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Human pituitary tumor-transforming gene 1 (PTTG1) encodes a securin protein critically important in regulating chromosome separation. Murine PTTG (mPTTG) is 66% homologous to human PTTG1 and PTTG-null (PTTGK/K) mice exhibit pancreatic b-cell hypoplasia and abnormal nuclear morphology with resultant diabetes. As we show that ductal b-cell neogenesis is intact in PTTGK/K mice, we explored mechanism for defective b-cell replication. We tested whether mPTTG exhibits securin properties in mouse insulin-secreting insulinoma MIN6 cells, using a live-cell system to monitor mitosis in cells transfected with an enhanced green fluorescent protein (EGFP)-tagged mPTTG conjugate (mPTTG-EGFP). To fulfill the criteria for securin properties, the protein should undergo degradation immediately before the metaphaseto-anaphase transition when expression levels are low, and should inhibit metaphase-to-anaphase transition when expression levels are high. EGFP itself did not undergo degradation throughout mitosis and high levels of EGFP per se did not affect normal mitosis progression (nZ25). However, mPTTG-EGFP was degraded 2 min before the metaphaseto-anaphase transition when expression levels were low (nZ19), and high mPTTG-EGFP levels blocked metaphaseto-anaphase transition in 13 cells. mPTTG-EGFP inhibited MIN6 cell proliferation and caused apoptosis. Immunocoprecipitation demonstrated binding of mPTTG-EGFP and separase. These results show that mPTTG exhibits properties consistent with a murine securin in insulin-secreting mouse cells and mPTTG overexpression inhibits cell proliferation, suggesting that defective b-cell proliferation observed in PTTGK/K mice is likely due to abnormal cell-cycle progression.

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Section: Resultsmentioning

confidence: 99%

Murine pituitary tumor-transforming gene functions as a securin protein in insulin-secreting cells

Yu¹,

Cruz²,

Calzi³

et al. 2006

Journal of Endocrinology

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“…PDX1 is essential for differentiation and maturation of pancreatic precursor cells towards β cells in the developing pancreas, and it is also the key regulator of insulin gene expression for postnatal β cell functions (1,2). During mouse early embryonic development, PDX1 expression can be firstly detected at embryonic day 8.5 in the dorsal and ventral buds that form pancreas; while in the adult stage, PDX1 is mainly expressed and functions in the β cells of the islet.…”

Section: Pdx1 and Pdx1 Involved Diseasesmentioning

confidence: 99%

PDX1 associated therapy in translational medicine

Yu¹,

Liu²,

Sanchez³

et al. 2016

Ann. Transl. Med.

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely poor prognosis and a low median survival due to lack of the early and reliable detection and effective therapeutic options, despite improvements observed for many other cancers in last decade. Pancreatic and duodenal homeobox 1 (PDX1), which is a homeodomain-containing transcription factor and a key regulator for insulin gene expression, β cell maturation and proper β cell function maintenance in the pancreas. Our previous studies revealed that PDX1 promotes tumorigenesis and it is a promising therapeutic target for PDAC. For translational purposes, we developed three therapeutic platforms utilizing RNA interference (RNAi), gene therapy and small inhibitory drug targeting PDX1, and further validated them in PDAC preclinical models both in vitro and in vivo. These PDX1 targeted therapies significantly inhibited PDX1 expression in PDAC cells, ablated PDX1-expressing human PDAC xenograft tumor growth, and prolonged survival in the PDAC mouse models. The data from these preclinical studies proved the translational potentials of PDX1 targeted therapies in PDAC and suggest that the strategy of developing PDX1 targeted therapies would permit a rapid bench-to-bedside translation of other relevant gene therapies, which would eventually benefit the patients suffering from this deadly disease.

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“…These organs are deformed in PDX1-deficient mice (2). As a transcription factor, the PDX-1 gene plays a critical role in embryological pancreas development and insulin expression in adult pancreatic islets (3,4). PDX-1 deficiency leads to duodenal and pancreatic ageing (5).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of pancreatic-duodenal homeobox 1 expression in breast cancer patients: A mechanism of proliferation and apoptosis in cancer

et al. 2012

Molecular Medicine Reports

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Abstract. Pancreatic-duodenal homeobox 1 (PDX-1) is a transcription factor that regulates embryological pancreas development and insulin expression in adult islets. The current study investigated the expression profile and potential role of PDX-1 in breast cancer. Immunohistochemistry was performed to determine the expression pattern of PDX-1 in breast cancer and adjacent benign breast tissues. In addition, cell proliferation and the cell cycle were evaluated following the transient inhibition of PDX-1 with antisense oligonucleotides in MCF-7 human breast cancer cells. Real-time PCR and western blotting were conducted to investigate the correlation between PDX-1, P53, Ki-67, Caspase 3 and Caspase 8. These experiments demonstrated that PDX-1 was downregulated in human breast cancer tissue compared with adjacent normal breast tissue. Knockdown of PDX-1 expression in vitro in MCF-7 breast cancer cells promoted cell proliferation and disrupted the cell cycle, as demonstrated by the overexpression of P53 and Ki-67 at the mRNA and protein levels. In conclusion, the current study shows that PDX-1 regulates cell proliferation and the cell cycle in human breast cancer cells by altering the expression of the cell cycle-related genes, P53 and Ki-67. These data suggest that PDX-1 is a putative tumor suppressor in breast cancer.

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PDX-1 and the Pancreas

Cited by 92 publications

References 110 publications

Murine pituitary tumor-transforming gene functions as a securin protein in insulin-secreting cells

Murine pituitary tumor-transforming gene functions as a securin protein in insulin-secreting cells

PDX1 associated therapy in translational medicine

Downregulation of pancreatic-duodenal homeobox 1 expression in breast cancer patients: A mechanism of proliferation and apoptosis in cancer

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