Downregulation of p53 by phosphatase of regenerating liver 3 is mediated by MDM2 and PIRH2

Min, Sang‐Hyun; Kim, Dong-Min; Heo, Young-Shin; Kim, Ho Min; Kim, Il-Chul; Yoo, Ook-Joon

doi:10.1016/j.lfs.2009.11.010

Cited by 36 publications

(39 citation statements)

References 33 publications

(47 reference statements)

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“…Our present studies show that loss of PTP4A3 alters ERK and p38 signaling. In addition, PTP4A3 has been shown to regulate p53 and p21 reporter activity (31). These results provide a potential mechanism for PTP4A3 regulation of proliferation and apoptosis in cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival

et al. 2016

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Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and women diagnosed with TNBC currently lack targeted treatment options. To identify novel targets for TNBC, we evaluated phosphatase expression in breast tumors and characterized their contributions to in vitro and in vivo growth of TNBC. Using Affymetrix microarray analysis of 102 breast cancers, we identified 146 phosphatases that were significantly differentially expressed in TNBC compared to estrogen receptor (ER)-positive tumors. Of these, 19 phosphatases were upregulated (0.66-fold; FDR=0.05) in TNBC compared to ER-positive breast cancers. We knocked down 17 overexpressed phosphatases in four triple-negative and four ER-positive breast cancer lines using specific small interfering RNAs and found that depletion of six of these phosphatases significantly reduced growth and anchorage-independent growth of TNBC cells to a greater extent than ER-positive cell lines. Further analysis of the phosphatase PTP4A3 (also known as PRL-3) demonstrated its requirement for G1/S cell cycle progression in all breast cancer cells, but PTP4A3 regulated apoptosis selectively in TNBC cells. In addition, PTP4A3 inhibition reduced the growth of TNBC tumors in vivo. Moreover, in silico analysis revealed the PTP4A3 gene to be amplified in 29% of basal-like breast cancers, and high expression of PTP4A3 could serve as an independent prognostic indicator for worse overall survival. Collectively, these studies define the importance of phosphatase overexpression in TNBC, and lay the foundation for the development of new targeted therapies directed against phosphatases or their respective signaling pathways for TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival

et al. 2016

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“…Those effects are mediated through several signaling pathways such as PI3K/Akt, Rho GTPase, cyclin-dependent kinase 2 (CDK2), angiotensin II and p53 signaling (9,(12)(13)(14)(15)19,23). The PI3K/Akt is an important signaling pathway in cell survival, and it is frequently activated in human cancers.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of phosphatase of regenerating liver gene family in non-small cell lung cancer

Lee

2011

Oncol Rep

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Abstract. Protein tyrosine phophatases (PTPs) are implicated in the tumorigenesis and metastasis of human cancer. The phosphatase of regenerating liver (PRL) gene family, a subgroup of PTPs is also linked to these processes. In many solid cancers, high levels of PRL-3 expression are related with metastasis and poor prognosis. However, the expression patterns of PRL-1 and -2 have not been explored in lung cancer yet. Thus, we investigated the expression levels of PRL-1, -2 and -3 in the tissues of primary lung cancer patients. The protein expression levels of PRL-2, but not PRL-1 and -3 were increased in cancer tissues. However, there was no correlation between mRNA and protein expression levels of the PRLs. Reporter assays showed that PRLs suppressed the activity of the p21 promoter but promoted AP-1 activity. Furthermore, transfection of PRLs showed significantly increased cell proliferation. Therefore, these results suggest that PRL-2 plays an important role in lung cancer and can be a biomarker of lung cancer, substituting for the function of other PRLs.

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Section: Cell Functionmentioning

confidence: 99%

“…Up-regulation of PRL-1 and −3 can both inhibit p53 and p53-mediated apoptosis individually with the opposite being true when PRL-1 or −3 is knocked down (62,63). Western blot analysis of PRL-1 or −3 overexpressing cells reveals that apoptosis inhibition can be caused by PRL-mediated activation of MDM2 via PI3K activation and PIRH2 (p53 ubiquitinase) transcription via EGR1 activation (62,63) (Figure 2). Min et al did not encounter the same cell cycle arrest phenotype that was discovered by Basak et al, however, this may be explained by carcinogenic defects in cancer cell lines used by Min et al (62,63).…”

Section: Cell Functionmentioning

confidence: 99%

Phosphatase of regenerating liver: a novel target for cancer therapy

Campbell

Zhang

2014

Expert Opinion on Therapeutic Targets

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Importance in the Field Phosphatases of Regenerating Liver (PRLs) are novel oncogenes that interact with many, well-established cell signaling pathways that are misregulated in cancer and is known to drive cancer metastasis when overexpressed. Areas Covered in this Review This review will cover basic information of the discovery and characteristics of the PRL family. We will also report findings on the role of PRL in cancer, cell functions, and cell signaling. Furthermore, PRL’s suitability as a novel drug target will be discussed along with current methods being developed to facilitate PRL inhibition. Expert Opinion PRLs show great potential as novel drug targets for anti-cancer therapeutics. Studies indicate that PRL can perturb major cancer pathways such as Src/ERK1/2 and PTEN/PI3K/Akt. Upregulation of PRLs has also been shown to drive cancer metastasis. However, in order to fully realize its therapeutic potential, a deeper understanding of the function of PRL in normal tissue and in cancer must be obtained. Novel and integrated biochemical, chemical biological and genetic approaches will be needed to identify PRL substrate(s) and to provide proof-of-concept data on the druggability of the PRL phosphatases.

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Downregulation of p53 by phosphatase of regenerating liver 3 is mediated by MDM2 and PIRH2

Cited by 36 publications

References 33 publications

Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival

Phosphatase PTP4A3 Promotes Triple-Negative Breast Cancer Growth and Predicts Poor Patient Survival

Altered expression of phosphatase of regenerating liver gene family in non-small cell lung cancer

Phosphatase of regenerating liver: a novel target for cancer therapy

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