ING2 controls the G<sub>1</sub>to S-phase transition by regulating p21 expression

Larrieu, Delphine; Ythier, Damien; Brambilla, Christian; Pedeux, Rémy

doi:10.4161/cc.9.19.13208

Cited by 25 publications

(32 citation statements)

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“…Lower levels of p53 and downstream p21 Cip-1 were induced in doxorubicin-resistant MCF-7 cells which also contain activated Akt-1[99]. p53 plays key roles in the regulation of cellular senescence [38-40,43-46,110-120], DNA damage response [121-123], cell cycle progression [124-143], chromosome dynamics [144-146], apoptosis [147-151], sensitivity to chemotherapy [152-154], radiotherapy [107,155] tumorigenesis and metastasis [53,156-158], metabolism [159-161], cellular redox [41,162], hypoxia [61,75,136,163,164], autophagy [49,165,166] and aging [167] as well as other important biological processes. Often some of the purported functions of p53 are overlapping and even sometimes contradictory.…”

Section: Discussionmentioning

confidence: 99%

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

et al. 2011

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Escape from cellular senescence induction is a potent mechanism for chemoresistance. Cellular senescence can be induced in breast cancer cell lines by the removal of estrogen signaling with tamoxifen or by the accumulation of DNA damage induced by the chemotherapeutic drug doxorubicin. Long term culturing of the hormone-sensitive breast cancer cell line MCF-7 in doxorubicin (MCF-7/DoxR) reduced the ability of doxorubicin, but not tamoxifen, to induce senescence. Two pathways that are often upregulated in chemo- and hormonal-resistance are the PI3K/PTEN/Akt/mTOR and Ras/Raf/MEK/ERK pathways. To determine if active Akt-1 and Raf-1 can influence drug-induced senescence, we stably introduced activated ΔAkt-1(CA) and ΔRaf-1(CA) into drug-sensitive and doxorubicin-resistant cells. Expression of a constitutively-active Raf-1 construct resulted in higher baseline senescence, indicating these cells possessed the ability to undergo oncogene-induced-senescence. Constitutive activation of the Akt pathway significantly decreased drug-induced senescence in response to doxorubicin but not tamoxifen in MCF-7 cells. However, constitutive Akt-1 activation in drug-resistant cells containing high levels of active ERK completely escaped cellular senescence induced by doxorubicin and tamoxifen. These results indicate that up regulation of the Ras/PI3K/PTEN/Akt/mTOR pathway in the presence of elevated Ras/Raf/MEK/ERK signaling together can contribute to drug-resistance by diminishing cell senescence in response to chemotherapy. Understanding how breast cancers containing certain oncogenic mutations escape cell senescence in response to chemotherapy and hormonal based therapies may provide insights into the design of more effective drug combinations for the treatment of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

et al. 2011

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“…More recently, a study from Larrieu found a novel and specific function of ING2 in regulation of G1/S transition. ING2 may regulate G1/S transition by mediating H3K4me3 at p21 promoter without p53 [31,32]. This study revealed the knockdown of ING2 may accelerate cell cycle progression, which provides evidence for the potential link between loss of ING2 and cancer development.…”

Section: Discussionmentioning

confidence: 63%

Decreased expression of ING2 gene and its clinicopathological significance in Chinese NSCLC patients

Pan¹,

Zhang²,

Xu³

et al. 2014

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The inhibitor of growth 2 (ING2) is a member of ING family, involved in cell cycle regulation, DNA repair, apoptosis and senescence, and participating in chromatin remodeling and transcriptional regulation by histone modification. Recent researches suggest ING2 plays roles in carcinogenesis both as tumor suppressor gene and ongocene depending on tumor types and cell status. Here, we investigated the status of ING2 in a series of 64 Chinese non-small cell lung cancer (NSCLC) patients using immunohistochemistry (IHC) and confirmed the results with Western blotting. RT-PCR results revealed the expression level of ING2 was consistent with mRNA level. The IHC results showed that ING2 protein expression was significantly decreased in NSCLC samples compared with normal lung tissues (P<0.05). ING2 expression was lost in 32.8% (21/64) NSCLC tissues, which was more frequently in adenocarcinoma (ADK) than in squamous cell carcinoma (SCC), 45.8% (11/24) and 26.3% (10/38), respectively. We also found ING2 translocation from the nucleus to the cytoplasm, which may be a critical event for carcinogenesis. And the status of ING2 in SCC was significantly associated with lymph node metastasis status and TNM stage. After sequencing ING2 gene, we found no heterozygosity or mutation. Taken together, these results indicated that the aberrantly expression of ING2 may contribute to NSCLC tumorigenesis. Key words: inhibitor of growth 2, non-small cell lung cancer, pathologyLung cancer remains the leading cause of cancer-related deaths worldwide [1]. Early diagnosis with surgical resection has a 67% 5-year survival [2]. However, the total 5-year survival rate of lung cancer cases was less than 17% [1], due to the lack of sensitive screening tests for early detection of lung cancer and ineffective treatment for advanced and metastatic disease [3]. Non-small-cell lung carcinoma (NSCLC) accounts for approximately 80% to 85% of all lung cancers. The development of NSCLC is a complex progress associated with multiple factors and stages, including accumulation of activation of oncogenes and inactivation of tumor suppressor genes [4]. Although several molecular predictors are being identified involving in lung tumorgenesis, others remain to be discovered [5]. Further researches on suppressor genes, apoptosis-related genes, and autophagy-related genes in the tumor progression of NSCLC will contribute to new strategies for early diagnosis, prognostic indictors and treatment of NSCLC [6].The inhibitor of growth family member 2 (ING2) was identified as a candidate of tumor suppressor by computational homology search with ING1 in 1998, mapped to chromosome 4q35.1 and localized to the subtelomeric region of chromosome 4 [7]. ING2 is comprised of three exons, exon 1a, 1b and 2, which encodes two isoforms, ING2a and ING2b, resulting from an alternative splicing between exons 1a and 1b [8]. The expression level of ING2b mRNA is much lower than ING2a, and ING2b protein has never been detected [9]. ING2a also called ING2 and ING1L, encodes a 33kDa protein ...

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“…It has been previously reported that ING2a is able to induce p21 [45]. However, it seems that the p21 induction by ING2a is dependent on the cellular context because LNCaP-ING1 KD cells showed no detectable change for p21 expression, but for p16 ( Fig.…”

Section: Ing1b Regulates the Stability Of Ing2a Proteinmentioning

confidence: 57%

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

et al. 2016

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ING2 controls the G₁to S-phase transition by regulating p21 expression

Cited by 25 publications

References 32 publications

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

Decreased expression of ING2 gene and its clinicopathological significance in Chinese NSCLC patients

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

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ING2 controls the G1to S-phase transition by regulating p21 expression

Cited by 25 publications

References 32 publications

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

Cooperative Effects of Akt-1 and Raf-1 on the Induction of Cellular Senescence in Doxorubicin or Tamoxifen Treated Breast Cancer Cells

Decreased expression of ING2 gene and its clinicopathological significance in Chinese NSCLC patients

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling

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ING2 controls the G₁to S-phase transition by regulating p21 expression