ING Proteins in Cellular Senescence

Menéndez, Camino; Abad, María; Gómez-Cabello, Daniel; Moreno, Alberto; Palmero, Ignacio

doi:10.2174/138945009788185077

Cited by 11 publications

(10 citation statements)

References 102 publications

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“…LHX3 is a homeodomain transcription factor and plays positive role in embryonic development, cell fate determination and oncogenesis [26], [27]. On the other hand, ING1, an ING family protein, is involved in human cellular senescence, tumor suppression and apoptosis [28], [29]. ING1 has been shown to modulate p53 activity and its downstream effectors, p21 WAF1 and Bax by acetylation and stabilization [30].…”

Section: Resultsmentioning

confidence: 99%

Selective Killing of Cancer Cells by Ashwagandha Leaf Extract and Its Component Withanone Involves ROS Signaling

et al. 2010

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Background and PurposeAshwagandha is a popular Ayurvedic herb used in Indian traditional home medicine. It has been assigned a variety of health-promoting effects of which the mechanisms remain unknown. We previously reported the selective killing of cancer cells by leaf extract of Ashwagandha (i-Extract) and its purified component Withanone. In the present study, we investigated its mechanism by loss-of-function screening (abrogation of i-Extract induced cancer cell killing) of the cellular targets and gene pathways.Methodology/Principal FindingsRandomized ribozyme library was introduced into cancer cells prior to the treatment with i-Extract. Ribozymes were recovered from cells that survived the i-Extract treatment. Gene targets of the selected ribozymes (as predicted by database search) were analyzed by bioinformatics and pathway analyses. The targets were validated for their role in i-Extract induced selective killing of cancer cells by biochemical and molecular assays. Fifteen gene-targets were identified and were investigated for their role in specific cancer cell killing activity of i-Extract and its two major components (Withaferin A and Withanone) by undertaking the shRNA-mediated gene silencing approach. Bioinformatics on the selected gene-targets revealed the involvement of p53, apoptosis and insulin/IGF signaling pathways linked to the ROS signaling. We examined the involvement of ROS-signaling components (ROS levels, DNA damage, mitochondrial structure and membrane potential) and demonstrate that the selective killing of cancer cells is mediated by induction of oxidative stress.ConclusionAshwagandha leaf extract and Withanone cause selective killing of cancer cells by induction of ROS-signaling and hence are potential reagents that could be recruited for ROS-mediated cancer chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Selective Killing of Cancer Cells by Ashwagandha Leaf Extract and Its Component Withanone Involves ROS Signaling

et al. 2010

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“…The expression of p33 ING1 protein can also slow cell growth, induce apoptosis, and promote the repair of damage. Its low expression may stimulate the formation of clones to promote the malignant transformation of cells, leading to tumorigenesis [18][19][20]. The mechanisms of losing the inhibitory ability of the p33 ING1 gene in tumor development and progression may include the following: decreased mRNA levels, abnormal gene function (such as gene rearrangement, mutation, promoter presence, CpG islands, and methylation), reduced protein levels and structural abnormalities, and binding with other biological macromolecules, such as p53 [28,29].…”

Section: Discussionmentioning

confidence: 99%

“…Many experiments, including those conducted in vivo and in vitro and in cells and in animals, have shown that the expression of p33 ING1 protein can slow cell growth, induce apoptosis, and promote damage repair. Its low expression can stimulate the formation of clones and promote the malignant transformation of cells, leading to tumorigenesis [18][19][20]. Gunduz et al [17,21] found that p33 ING1 is a molecular chaperone of p53.…”

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confidence: 99%

The expression of p33ING1, p53, and autophagy-related gene Beclin1 in patients with non-small cell lung cancer

et al. 2011

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The purpose of this study was to investigate the expressions of tumor inhibitor of growth (ING1) gene p33ING1, p53, and autophagy-related gene Beclin1 in human non-small cell lung cancer (NSCLC), and the correlation between their expressions with clinical pathological features and clinical significance. The research can provide new ideas and experimental evidence for early diagnosis and biotherapy for NSCLC in the future. The human NSCLC tissues and surrounding non-cancerous tissues were collected from surgical operation. The expressions of mRNA or protein of p33ING1, p53, and Beclin1 were detected by using of reverse transcription polymerase chain reaction or Western blot in these tissues. The results were used to analyze the relationships between these gene expressions with the developing of NSCLC and clinical pathological features. The expressions of mRNA or protein of p33ING1 and Beclin1 in NSCLC tissues were significantly lower than that in surrounding noncancerous tissues (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in well- and middle-differentiated NSCLC tissues were lower than those in poor-differentiated NSCLC tissues (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in presence of lymph nodes metastasis were lower than those in absence of lymph nodes metastasis (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in patients of pathological stage (stages I-II) were higher than those in pathological stage (stages III-IV) (p < 0.05). But the expression of protein of mutant-type p53 in NSCLC tissues was significantly higher than that in surrounding non-cancerous tissues (p < 0.05). The expressions of protein of mutant-type p53 in well- and middle-differentiated NSCLC tissues were higher than those in poor-differentiated NSCLC tissues (p < 0.05). The expressions of protein of mutant-type p53 in presence of lymph nodes metastasis were higher than those in absence of lymph nodes metastasis (p < 0.05). The expressions of protein of mutant-type p53 in patients of pathological stage (stages I-II) were lower than those in pathological stage (stages III-IV) (p < 0.05). These expression changes of p33ING1, p53, and autophagy-related Beclin1 genes were associated with tumor cell differentiation, lymph nodes metastasis, and pathological stage of NSCLC. But these expression changes of these three genes were not associated with gender, age, size of primary carcinoma, histological type of NSCLC (p > 0.05). The expression of mRNA of p53 and Beclin1 were correlated with p33ING1 mRNA expression in NSCLC tissues (p < 0.05). The activity changes of tumor inhibitor of growth, autophagy, and apoptosis may be related to the emergence and the development of NSCLC. The combined detection of p33ING1, p53, and Beclin1 genes and proteins will be helpful for early diagnosis and prognosis judgment for NSCLC, and can provide experimental evidence for biotherapy of NSCLC.

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“…ING proteins are implicated in the control of several key cellular processes including proliferation, apoptosis, DNA repair, senescence, and drug resistance; also their transcript levels are often reduced in cancer cells [1]–[3]. The latter property likely results from epigenetic regulation of the ING genes through events such as DNA hypermethylation, as mutations in these genes are rare [4].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Thyroid Hormone-Dependent Gene Expression in Xenopus laevis by INhibitor of Growth (ING) Proteins

Helbing

Wagner²,

Pettem³

et al. 2011

PLoS ONE

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BackgroundINhibitor of Growth (ING) proteins belong to a large family of plant homeodomain finger-containing proteins important in epigenetic regulation and carcinogenesis. We have previously shown that ING1 and ING2 expression is regulated by thyroid hormone (TH) during metamorphosis of the Xenopus laevis tadpole. The present study investigates the possibility that ING proteins modulate TH action.Methodology/Principal FindingsTadpoles expressing a Xenopus ING2 transgene (TransING2) were significantly smaller than tadpoles not expressing the transgene (TransGFP). When exposed to 10 nM 3,5,3′-triiodothyronine (T3), premetamorphic TransING2 tadpoles exhibited a greater reduction in tail, head, and brain areas, and a protrusion of the lower jaw than T3-treated TransGFP tadpoles. Quantitative real time polymerase chain reaction (QPCR) demonstrated elevated TH receptor β (TRβ) and TH/bZIP transcript levels in TransING2 tadpole tails compared to TransGFP tadpoles while TRα mRNAs were unaffected. In contrast, no difference in TRα, TRβ or insulin-like growth factor (IGF2) mRNA abundance was observed in the brain between TransING2 and TransGFP tadpoles. All of these transcripts, except for TRα mRNA in the brain, were inducible by the hormone in both tissues. Oocyte transcription assays indicated that ING proteins enhanced TR-dependent, T3-induced TRβ gene promoter activity. Examination of endogenous T3-responsive promoters (TRβ and TH/bZIP) in the tail by chromatin immunoprecipitation assays showed that ING proteins were recruited to TRE-containing regions in T3-dependent and independent ways, respectively. Moreover, ING and TR proteins coimmunoprecipitated from tail protein homogenates derived from metamorphic climax animals.Conclusions/SignificanceWe show for the first time that ING proteins modulate TH-dependent responses, thus revealing a novel role for ING proteins in hormone signaling. This has important implications for understanding hormone influenced disease states and suggests that the induction of ING proteins may facilitate TR function during metamorphosis in a tissue-specific manner.

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ING Proteins in Cellular Senescence

Cited by 11 publications

References 102 publications

Selective Killing of Cancer Cells by Ashwagandha Leaf Extract and Its Component Withanone Involves ROS Signaling

Selective Killing of Cancer Cells by Ashwagandha Leaf Extract and Its Component Withanone Involves ROS Signaling

The expression of p33ING1, p53, and autophagy-related gene Beclin1 in patients with non-small cell lung cancer

Modulation of Thyroid Hormone-Dependent Gene Expression in Xenopus laevis by INhibitor of Growth (ING) Proteins

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