Lack of expression for the suppressor PML in human small cell lung carcinoma

Zhang, Ping; Chin, Wai; Chow, Louis T. C.; Chan, Alex W.H.; Yim, Anthony P.C.; Leung, Sing Fai; Mok, Tony; Chang, Kung Sang; Johnson, Philip J.; Chan, John Y.H.

doi:10.1002/(sici)1097-0215(20000301)85:5<599::aid-ijc1>3.0.co;2-#

Cited by 48 publications

(28 citation statements)

References 15 publications

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“…While a lack of expression was apparent at the protein level, PML mRNA appeared to be normally expressed, and no mutations were found in any of the samples analyzed [73]. Additionally, immunohistochemistry studies have shown loss of PML expression in breast carcinomas [44], gastric cancer [74], small cell lung carcinoma [75], and in invasive epithelial tumors [76]. Interestingly, Gurrieri et al demonstrated that loss of PML correlates with higher tumor grading in breast adenocarcinomas, prostate carcinomas, and CNS tumors, which confirmed previous data from gastric cancers [73,74].…”

Section: Pml Role In Cancersupporting

confidence: 64%

The Role of PML in the Nervous System

Salomoni¹,

Betts-Henderson

2010

Mol Neurobiol

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The promyeloctic leukemia protein PML is a tumor suppressor that was originally identified due to its involvement in the (15;17) translocation of acute promyelocytic leukemia. While the majority of early research has focused upon the role of PML in the pathogenesis of leukemia, more recent evidence has identified important roles for PML in tissues outside the hemopoietic system, including the central nervous system (CNS). Here, we review recent literature on the role of PML in the CNS, with particular focus on the processes of neurodevelopment and neurodegeneration, and propose new lines of investigation.

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Section: Pml Role In Cancersupporting

confidence: 64%

The Role of PML in the Nervous System

Salomoni¹,

Betts-Henderson

2010

Mol Neurobiol

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“…However, due to the unusual caspase-independent nature of the Bin1 death phenotype in malignant cells, we are addressing this question further using cells targeted for Bin1 gene deletion. In summary, despite the key role of apoptotic escape in malignant development, it is notable that caspases and other apoptosome components may be inactivated in cancer cells less frequently than caspaseindependent functions such as Pml or Bin1 (Ge et al, 1999(Ge et al, , 2000aMu et al, 1994;Sakamuro et al, 1996;Zhang et al, 2000). Our ®ndings suggest that Bin1 participates in some caspase-independent process which can in¯uence cell death commitment in malignant cells.…”

Section: Independence From Mitochondrial Processes and Caspasesmentioning

confidence: 66%

The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program

et al. 2000

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Cell death processes are progressively inactivated during malignant development, in part by loss of tumor suppressors that can promote cell death. The Bin1 gene encodes a nucleocytosolic adaptor protein with tumor suppressor properties, initially identi®ed through its ability to interact with and inhibit malignant transformation by c-Myc and other oncogenes. Bin1 is frequently missing or functionally inactivated in breast and prostate cancers and in melanoma. In this study, we show that Bin1 engages a caspase-independent cell death process similar to type II apoptosis, characterized by cell shrinkage, substratum detachment, vacuolated cytoplasm, and DNA degradation. Cell death induction was relieved by mutation of the BAR domain, a putative e ector domain, or by a missplicing event that occurs in melanoma and inactivates suppressor activity. Cells in all phases of the cell cycle were susceptible to death and p53 and Rb were dispensable. Notably, Bin1 did not activate caspases and the broad spectrum caspase inhibitor ZVAD.fmk did not block cell death. Consistent with the lack of caspase involvement, dying cells lacked nucleosomal DNA cleavage and nuclear lamina degradation. Moreover, neither Bcl-2 or dominant inhibition of the Fas pathway had any e ect. In previous work, we showed that Bin1 could not suppress cell transformation by SV40 large T antigen. Consistent with this ®nding, we observed that T antigen suppressed the death program engaged by Bin1. This observation was interesting in light of emerging evidence that T antigen has roles in cell immortalization and human cell transformation beyond Rb and p53 inactivation. In support of a link to c-Mycinduced death processes, AEBSF, a serine protease inhibitor that inhibits apoptosis by c-Myc, potently suppressed DNA degradation by Bin1. Our ®ndings suggest that the tumor suppressor activity of Bin1 re¯ects engagement of a unique cell death program. We propose that loss of Bin1 may promote malignancy by blunting death penalties associated with oncogene activation. Oncogene (2000) 19, 4669 ± 4684.

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“…We would propose that post-translational proteasome-dependent degradation explains the loss of PML protein. In other words, degradation at the transcriptional level is not operative [2], [44]. PML protein expression is reduced or abolished in many different cancers, including prostate, breast, CNS, colon, lung, and gastric cancer [2], [3].…”

Section: Discussionmentioning

confidence: 99%

Loss of the Promyelocytic Leukemia Protein in Gastric Cancer: Implications for IP-10 Expression and Tumor-Infiltrating Lymphocytes

et al. 2011

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Gastric cancer is one of the most common causes of cancer-related mortality worldwide. Expression of the tumor suppressor, promyelocytic leukemia (PML) protein, is reduced or abolished in gastric carcinomas, in association with an increased level of lymphatic invasion, development of higher pTNM staging, and unfavorable prognosis. Herein, we investigated the relationship between the extent of tumor-infiltrating lymphocytes and the status of PML protein expression in advanced gastric carcinoma. We observed higher numbers of infiltrating T-cells in gastric carcinoma tissues in which PML expression was reduced or abolished, compared to tissues positive for PML. The extent of T-cell migration toward culture supernatants obtained from interferon-gamma (IFN-γ-stimulated gastric carcinoma cell lines was additionally affected by expression of PML in vitro. Interferon-gamma-inducible protein 10 (IP-10/CXCL10) expression was increased in gastric carcinoma tissues displaying reduced PML levels. Moreover, both Pml knockout and knockdown cells displayed enhanced IP-10 mRNA and protein expression in the presence of IFN-γ. PML knockdown increased IFN-γ-mediated Signal Transducer and Activator of Transcription-1 (STAT-1) binding to the IP-10 promoter, resulting in elevated transcription of the IP-10 gene. Conversely, PML IV protein expression suppressed IP-10 promoter activation. Based on these results, we propose that loss of PML protein expression in gastric cancer cells contributes to increased IP-10 transcription via enhancement of STAT-1 activity, which, in turn, promotes lymphocyte trafficking within tumor regions.

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Lack of expression for the suppressor PML in human small cell lung carcinoma

Cited by 48 publications

References 15 publications

The Role of PML in the Nervous System

The Role of PML in the Nervous System

The c-Myc-interacting adaptor protein Bin1 activates a caspase-independent cell death program

Loss of the Promyelocytic Leukemia Protein in Gastric Cancer: Implications for IP-10 Expression and Tumor-Infiltrating Lymphocytes

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