ING1 and ING2: Multi-Faceted Tumor Suppressor Genes

International audienceING1 (Inhibitor of Growth 1) was identified and characterized as a "candidate" tumor suppressor gene in 1996. Subsequently four more genes, also characterized as "candidate" tumor suppressor genes, were identified by homology search: ING2, ING3, ING4 and ING5. The ING proteins are characterized by a high homology in their C-terminal domain which contains a Nuclear Localization Sequence (NLS) and a Plant HomeoDomain (PHD) which has a high affinity to Histone 3 tri-methylated on lysine 4 (H3K4Me3). The ING proteins have been involved in the control of cell growth, senescence, apoptosis, chromatin remodelling and DNA repair. Within the ING family, ING1 and ING2 form a subgroup since they are evolutionarily and functionally close. In Yeast, only one gene, Pho23, is related to ING1 and ING2 and possesses also a PHD. Recently, the ING1 and ING2 tumor suppressor status has been fully established since several studies have described the loss of ING1 and ING2 protein expression in human tumors and both ING1 and ING2 knockout mice were reported to have spontaneously developed tumors, B-cell lymphomas and soft tissue sarcomas respectively. In this review we will describe for the first time what is known about ING1 and ING2 genes, proteins, their regulations in both human and mice, and their status in human tumors. Furthermore, we explore the current knowledge about identified functions involving ING1 and ING2 in tumor suppression pathways especially in the control of cell cycle and in genome stability

SharING out the roles in replicatING DNA.

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The ING tumor suppressor genes: status in human tumors.

International audienceING genes (ING1-5) were identified has tumor suppressor genes. ING proteins are characterized as Type II TSGs since they are involved in the control of cell proliferation, apoptosis and senescence. They may also function as Type I TSGs since they are also involved in DNA replication and repair. Most studies have reported that they are frequently lost in human tumors and epigenetic mechanisms or misregulation of their transcription may be involved. Recently, studies have described that this loss may be caused by microRNA inhibition. Here, we summarize the current knowledge on ING functions, their involvement in tumor suppression and, in order to give a full assessment of the current knowledge, we review all the studies that have examined ING status in human cancers

ING2 controls the G1 to S-phase transition by regulating p21 expression.

International audienceING2 (Inhibitor of Growth 2) is a candidate tumor suppressive protein frequently lost in human tumors. Recently, we have reported that ING2 downregulation impairs DNA replication forks progression and leads to genome instability. To better understand the tumor suppressive functions of ING2 and its role in the cell cycle, we downregulated its expression in cells and studied the consequences of this downregulation on the G(1)/S transition. We observed that the inhibition of ING2 expression accelerated the progression of cells from G(1) to S-phase, and was accompanied by a decrease of p21 expression. Moreover, we show that the regulation of p21 by ING2 is independent of the tumor suppressive protein p53. Interestingly, this function seems to be unique for ING2 since its closest homolog ING1 does not regulate the G(1)/S transition. It has been suggested previously that ING2 may modulate the trimethylation of H3K4 at the promoter of p21. Accordingly, our results suggest that there may be a link between the regulation of the G(1)/S transition by ING2 and the level of H3K4Me3. All together, these results bring new information concerning the role of ING2 in the regulation of the cell cycle and suggest that it may play important roles in controlling several S-phase checkpoints

Hypoxia differentially modulates the genomic stability of clinical-grade ADSCs and BM-MSCs in long-term culture

International audienceLong-term cultures under hypoxic conditions have been demonstrated to maintain the phenotype of mesenchymal stromal/stem cells (MSCs) and to prevent the emergence of senescence. According to several studies, hypoxia has frequently been reported to drive genomic instability in cancer cells and in MSCs by hindering the DNA damage response and DNA repair. Thus, we evaluated the occurrence of DNA damage and repair events during the ex vivo expansion of clinical-grade adipose-derived stromal cells (ADSCs) and bone marrow (BM)-derived MSCs cultured with platelet lysate under 21% (normoxia) or 1% (hypoxia) O2 conditions. Hypoxia did not impair cell survival after DNA damage, regardless of MSC origin. However, ADSCs, unlike BM-MSCs, displayed altered γH2AX signaling and increased ubiquitylated γH2AX levels under hypoxic conditions, indicating an impaired resolution of DNA damage-induced foci. Moreover, hypoxia specifically promoted BM-MSC DNA integrity, with increased Ku80, TP53BP1, BRCA1 and RAD51 expression levels and more efficient non-homologous end joining and homologous recombination repair. We further observed that hypoxia favored mtDNA stability and maintenance of differentiation potential after genotoxic stress. We conclude that long-term cultures under 1% O2 were more suitable for BM-MSCs as suggested by improved genomic stability compared with ADSCs. This article is protected by copyright. All rights reserved

Sex differences in numbers of nevi on body sites of young European children: Implications for the etiology of cutaneous melanoma

Background: Since 1950, the greatest increase in cutaneous melanoma incidence in fair-skinned males took place on the trunk and on the head and neck, whereas in females, it took place on the limbs, mainly on the lower limbs. We examined the influence of sex on numbers and size of nevi on different body sites in white European schoolchildren. Methods: Information about each holiday period since birth to interview was recorded from parents of six hundred twenty-eight 6- to 7-year-old children in four European cities (Brussels (Belgium), Bochum (Germany), Lyons (France), and Rome (Italy)). Number and anatomic location of small (2-4.9 mm) and large (≥5 mm) nevi and individual susceptibility to sunlight were independently assessed. Results: After adjustment for host characteristics, sun exposure, and sun protection habits, males had 7% [95% confidence interval (95% CI), -7 to 19] more small nevi than females. However, compared to females, numbers of small nevi were increased by 17% (95% CI, 1-31) on the head and neck and by 16% (95% CI, 2-27) on the trunk and shoulders. In contrast, in males, the number of small nevi on upper limbs was decreased by -5% (95% CI, -26 to 13), and on lower limbs by -8% (95% CI, -34 to 13). The number of large nevi was 6% higher in males than in females (95% CI, -26 to 30). Conclusions: The sex differences in small nevus distribution in schoolchildren reflect the sex differences in the anatomic distribution of melanoma in adults. Sex differences in sun exposure behaviors, dressing, and clothing would just add their effects to the sex-dependent inherited propensity to develop nevi on a given body site. These results reinforce the hypothesis by which childhood would be a decisive period for the occurrence of sun-induced biological events implicated in the genesis of cutaneous melanoma.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

ING2 controls the progression of DNA replication forks to maintain genome stability

Inhibitor of growth 2 (ING2) is a candidate tumour suppressor gene the expression of which is frequently lost in tumours. Here, we identified a new function for ING2 in the control of DNA replication and in the maintenance of genome stability. Global replication rate was markedly reduced during normal S-phase in small interfering RNA (siRNA) ING2 cells, as seen in a DNA fibre spreading experiment. Accordingly, we found that ING2 interacts with proliferating cell nuclear antigen and regulates its amount to the chromatin fraction, allowing normal replication progression and normal cell proliferation. Deregulation of DNA replication has been previously associated with genome instability. Hence, a high proportion of siRNA ING2 cells presented endoreduplication of their genome as well as an increased frequency of sister chromatid exchange. Thus, we propose for the first time that ING2 might function as a tumour suppressor gene by directly maintaining DNA integrity