The ING1a Tumor Suppressor Regulates Endocytosis to Induce Cellular Senescence Via the Rb-E2F Pathway

Rajarajacholan, Uma Karthika; Thalappilly, Subhash; Riabowol, Karl

doi:10.1371/journal.pbio.1001502

Cited by 33 publications

(40 citation statements)

References 80 publications

(91 reference statements)

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“…Conversely, EGCG may directly inhibit DNMT activity, inducing reactivation of methylationsilenced genes as previously reported (10,(31)(32)(33)(34). Direct interaction of EGCG to the catalytic site of DNMT 1 has been reported (32), in addition to oxidation of DNMT by EGCG (20). Furthermore, inhibition of HDACs by EGCG has been reported (21).…”

Section: Discussionmentioning

confidence: 64%

“…Reduced p16 INK4a expression may result in sustained binding of CDK4/CDK6 to cyclin D and subsequent phosphorylation of Rb protein, resulting in uncontrolled cell proliferation (2,3). p16 INK4a expression may also mediate cell senescence (5,20); it may also inhibit cell growth by directly interacting with the eukaryotic elongation factor 1A2 (eEF1A2), reducing its expression (4). In addition, EGCG-induced apoptosis of Jurkat cells through hydrogen peroxide production has been demonstrated (21).…”

Section: Discussionmentioning

confidence: 99%

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Epigallocatechin-3-gallate and trichostatin A synergistically inhibit human lymphoma cell proliferation through epigenetic modification of p16INK4a

Shen

et al. 2013

Oncology Reports

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DNA methylation and histone deacetylation play important roles in the occurrence and development of cancers by inactivating the expression of tumor suppressors, including p16(INK4a), a cyclin-dependent kinase inhibitor. The present study investigated the effect of epigallocatechin-3-gallate (EGCG) alone or in combination with trichostatin A (TSA) on p16(INK4a) gene expression and growth in human malignant lymphoma CA46 cells. CA46 cell viability and cell cycle were analyzed; methylation of the p16(INK4a) gene was assessed by nested methylation-specific PCR (n-MSP). p16(INK4a )mRNA and protein expression was determined by real-time quantitative PCR and western blot analyses, respectively. Both EGCG and TSA alone inhibited CA46 cell proliferation; the combined treatment (6 µg/ml EGCG and 15 ng/ml TSA) significantly reduced CA46 cell proliferation from 24 to 96 h (all P<0.001). Cells treated with 24 µg/ml EGCG or the combination treatment (6 µg/ml EGCG and 15 ng/ml TSA) had lower proliferative indices when compared to the other groups. Co-treatment with EGCG and TSA decreased p16(INK4a) gene methylation, which coincided with increased p16(INK4a) mRNA and protein expression. Thus, EGCG and TSA synergistically reactivate p16(INK4a) gene expression in part through reducing promoter methylation, which may decrease CA46 cell proliferation.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Epigallocatechin-3-gallate and trichostatin A synergistically inhibit human lymphoma cell proliferation through epigenetic modification of p16INK4a

Shen

et al. 2013

Oncology Reports

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“…However, they exert different roles since ING1a overexpression leads to a decreased histone acetylation whereas ING1b overexpression induces H3 and H4 hyperacetylation [24]. In addition, ING1a is rather involved in senescent cells pathways [25,26]. For these reasons, we will focus here on ING1b.…”

Section: Ing1 Participates In H3 and H4 Acetylationmentioning

confidence: 99%

Focus-ING on DNA Integrity: Implication of ING Proteins in Cell Cycle Regulation and DNA Repair Modulation

Archambeau

Blondel

Pedeux

2019

Cancers

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The ING family of tumor suppressor genes is composed of five members (ING1-5) involved in cell cycle regulation, DNA damage response, apoptosis and senescence. All ING proteins belong to various HAT or HDAC complexes and participate in chromatin remodeling that is essential for genomic stability and signaling pathways. The gatekeeper functions of the INGs are well described by their role in the negative regulation of the cell cycle, notably by modulating the stability of p53 or the p300 HAT activity. However, the caretaker functions are described only for ING1, ING2 and ING3. This is due to their involvement in DNA repair such as ING1 that participates not only in NERs after UV-induced damage, but also in DSB repair in which ING2 and ING3 are required for accumulation of ATM, 53BP1 and BRCA1 near the lesion and for the subsequent repair. This review summarizes evidence of the critical roles of ING proteins in cell cycle regulation and DNA repair to maintain genomic stability.

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“…They differ in their N‐termini (Fig. 1) and growth‐regulatory effects, with ING1a affecting cell senescence [64,65] and ING1b contributing to apoptosis [54,58,66–69]. Over almost two decades of study, ING1 was initially identified as a type‐II tumor suppressor, then also as an inducer of replicative senescence and more recently as a transcriptional regulator.…”

Section: Almost Two Decades Of Learning: From Candidate Tumor Suppresmentioning

confidence: 99%

“…Overexpression of human ING1 causes cell‐cycle arrest in the G 0 /G 1 ‐phase, whereas suppression leads to loss of cellular growth control and immortalisation [20]. While ING1b is mainly involved in regulating apoptosis, cellular stress, hormonal responses as well as inhibition of tumor angiogenesis [105–107], ING1a inhibits growth by inducing replicative senescence, partially through inhibiting endocytosis via the Rb‐tumor‐suppressor pathway [64,65]. ING1b can efficiently induce apoptosis through interaction with other tumor suppressors like p53 [68,108,109] and with members of the intrinsic apoptotic pathway such as BCL‐2‐associated X protein (BAX) [69].…”

Section: Almost Two Decades Of Learning: From Candidate Tumor Suppresmentioning

confidence: 99%

Keep‐ING balance: Tumor suppression by epigenetic regulation

Tallen

Riabowol

2014

FEBS Letters

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a b s t r a c tCancer cells accumulate genetic and epigenetic changes that alter gene expression to drive tumorigenesis. Epigenetic silencing of tumor suppressor, cell cycle, differentiation and DNA repair genes contributes to neoplastic transformation.The ING (inhibitor of growth) proteins (ING1-ING5) have emerged as a versatile family of growth regulators, phospholipid effectors, histone mark sensors and core components of HDAC1/2 -and several HAT chromatin-modifying complexes. This review will describe the characteristic pathways by which ING family proteins differentially affect the Hallmarks of Cancer and highlight the various epigenetic mechanisms by which they regulate gene expression. Finally, we will discuss their potentials as biomarkers and therapeutic targets in epigenetic treatment strategies.

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The ING1a Tumor Suppressor Regulates Endocytosis to Induce Cellular Senescence Via the Rb-E2F Pathway

Abstract: An age-associated isoform of ING1, ING1a, induces cell senescence by altering endocytosis, subsequently activating the retinoblastoma tumor suppressor.

Cited by 33 publications

References 80 publications

Epigallocatechin-3-gallate and trichostatin A synergistically inhibit human lymphoma cell proliferation through epigenetic modification of p16INK4a

Epigallocatechin-3-gallate and trichostatin A synergistically inhibit human lymphoma cell proliferation through epigenetic modification of p16INK4a

Focus-ING on DNA Integrity: Implication of ING Proteins in Cell Cycle Regulation and DNA Repair Modulation

Keep‐ING balance: Tumor suppression by epigenetic regulation

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