The ING tumor suppressors in cellular senescence and chromatin

<p>Abstract</p> <p>The Inhibitor of Growth (ING) proteins represent a type II tumor suppressor family comprising five conserved genes, <it>ING1 </it>to <it>ING5</it>. While ING1, ING2 and ING3 proteins are stable components of the mSIN3a-HDAC complexes, the association of ING1, ING4 and ING5 with HAT protein complexes was also reported. Among these the ING1 and ING2 have been analyzed more deeply. Similar to other tumor suppressor factors the ING proteins are also involved in many cellular pathways linked to cancer and cell proliferation such as cell cycle regulation, cellular senescence, DNA repair, apoptosis, inhibition of angiogenesis and modulation of chromatin.</p> <p>A common structural feature of ING factors is the conserved plant homeodomain (PHD), which can bind directly to the histone mark trimethylated lysine of histone H3 (H3K4me3). PHD mutants lose the ability to undergo cellular senescence linking chromatin mark recognition with cellular senescence. ING1 and ING2 are localized in the cell nucleus and associated with chromatin modifying enzymes, linking tumor suppression directly to chromatin regulation. In line with this, the expression of ING1 in tumors is aberrant or identified point mutations are mostly localized in the PHD finger and affect histone binding. Interestingly, ING1 protein levels increase in replicative senescent cells, latter representing an efficient pathway to inhibit cancer proliferation. In association with this, suppression of p33ING1 expression prolongs replicative life span and is also sufficient to bypass oncogene-induced senescence. Recent analyses of ING1- and ING2-deficient mice confirm a tumor suppressive role of ING1 and ING2 and also indicate an essential role of ING2 in meiosis.</p> <p>Here we summarize the activity of ING1 and ING2 as tumor suppressors, chromatin factors and in development.</p

The role of 99mTc-Ubiquicidin (UBI) and 99mTc-IgG scintigraphies in diagnosis of acute appendicitis: A preliminary result

Introduction: Appendicitis is one of the most common surgical emergencies. In spite of the relatively high rate of negative appendectomy, as a result of miss diagnosis, uncertainty of diagnosis still continues to challenge physicians. The objective of this prospective study was to investigate the role of 99mTc-Ubiquicidin (UBI) scintigraphy in the diagnosis of acute appendicitis and to compare 99mTc-UBI scintigraphy with 99mTc-IgG scintigraphy. Methods: Twelve patients with right lower quadrant pain and suspicious of acute appendicitis were referred to the nuclear medicine imaging center. Radionuclide imaging was performed with 99mTc-UBI in 8 and 99mTc-IgG in 4 patients. Ultrasonography, Alvarado scoring and histopathological examinations were also performed as additional diagnostic tests. Results: Reports from 99mTc-IgG and 99mTc-UBI scintigraphies of all patients were negative. Conclusion: This study may conclude that 99mTc-IgG scintigraphy and 99mTc-UBI scintigraphy in the detection of appendicitis do not have adequate efficacy. However, in order to better evaluate 99mTc-IgG and 99mTc-UBI scintigraphy, a comprehensive study on a large number of patients with clinical suspicious of acute appendicitis would be more helpful

Inhibitor of Growth Factors Regulate Cellular Senescence

Simple Summary Five members of the Inhibitor of Growth (ING) family share a highly conserved plant homeodomian with affinity to the specific histone modification H3K4me3. Since some ING family members are preferentially associated with histone acetyltransferaseactivity while other members with histone deacetlyse activity, the ING family membres are epigenetic regulators. Interestingly, ING members can regulate the induction cellular senescence in both primray untransformed human cells as well as human cancer cells. We discuss here the up-to-date knowledge about their regulatory activity within the cellular senescent program. Abstract The Inhibitor of Growth (ING) proteins are a group of tumor suppressors with five conserved genes. A common motif of ING factors is the conserved plant homeodomain (PHD), with which they bind to chromatin as readers of the histone mark trimethylated histone H3 (H3K4me3). These genes often produce several protein products through alternative splicing events. Interestingly, ING1 and ING2 participate in the establishment of the repressive mSIN3a-HDAC complexes, whereas ING3, ING4, and ING5 are associated with the activating HAT protein complexes. In addition to the modulation of chromatin’s structure, they regulate cell cycle transition, cellular senescence, repair of DNA damage, apoptosis, and angiogenic pathways. They also have fundamental effects on regulating cellular senescence in cancer cells. In the current review, we explain their role in cellular senescence based on the evidence obtained from cell line and animal studies, particularly in the context of cancer

Portulaca oleracea seeds extract does not prevent dexamethasone-induced hypertension in rats

Introduction: Portulaca oleracea is used as a nutritional and medicinal plant. The aim of this study was to assess the effect of hydroalcoholic extract of P. oleracea seeds in dexamethasone -induced hypertension in rats. Methods: For induction of hypertension, dexamethasone (30 µg/kg/d, subcutaneously) was administered for 14 days. Animals received P. oleracea extract as a pretreatment at various doses of 100, 200 and 400 mg/kg/d orally from 4 days before dexamethasone administration and during the test period. Systolic blood pressure (SBP) and heart rate were measured using tailcuff method. The weight of thymus gland was estimated as a marker of glucocorticoid activity. Results: Dexamethasone injection significantly increased SBP (P < 0.001) while decreased the body and thymus weights (P < 0.05 and P < 0.001, respectively). Oral administration of P. oleracea could not prevent rising in SBP and decreasing in thymus weight. It also increased heart rate in hypertensive rats at the dose of 400 mg/kg/d (P < 0.05). Conclusion: The results of this study revealed that hydroalcoholic extract of P. oleracea seeds aggregates hypertension in dexamethasone-induced hypertensive rats. Hence, it should be used with caution in hypertensive patients receiving glucocorticoids

ING2 (inhibitor of growth family, member 2)

Review on ING2 (inhibitor of growth family, member 2), with data on DNA, on the protein encoded, and where the gene is implicated

Interaction between Non-Coding RNAs and Androgen Receptor with an Especial Focus on Prostate Cancer

The androgen receptor (AR) is a member of the nuclear receptor superfamily and has three functional domains, namely the N-terminal, DNA binding, and C-terminal domain. The N-terminal domain harbors potent transactivation functions, whereas the C-terminal domain binds to androgens and antiandrogens used to treat prostate cancer. AR has genomic activity being DNA binding-dependent or through interaction with other DNA-bound transcription factors, as well as a number of non-genomic, non-canonical functions, such as the activation of the ERK, AKT, and MAPK pathways. A bulk of evidence indicates that non-coding RNAs have functional interactions with AR. This type of interaction is implicated in the pathogenesis of human malignancies, particularly prostate cancer. In the current review, we summarize the available data on the role of microRNAs, long non-coding RNAs, and circular RNAs on the expression of AR and modulation of AR signaling, as well as the effects of AR on their expression. Recognition of the complicated interaction between non-coding RNAs and AR has practical importance in the design of novel treatment options, as well as modulation of response to conventional therapeutics

Emerging Role of Non-Coding RNAs in Senescence

Senescence is defined as a gradual weakening of functional features of a living organism. Cellular senescence is a process that is principally aimed to remove undesirable cells by prompting tissue remodeling. This process is also regarded as a defense mechanism induced by cellular damage. In the course of oncogenesis, senescence can limit tumor progression. However, senescence participates in the pathoetiology of several disorders such as fibrotic disorders, vascular disorders, diabetes, renal disorders and sarcopenia. Recent studies have revealed contribution of different classes of non-coding RNAs in the cellular senescence. Long non-coding RNAs, microRNAs and circular RNAs are three classes of these transcripts whose contributions in this process have been more investigated. In the current review, we summarize the available literature on the impact of these transcripts in the cellular senescence

A review on the role of long non-coding RNA prostate androgen-regulated transcript 1 (PART1) in the etiology of different disorders

LncRNA prostate androgen-regulated transcript 1 (PART1) is an important lncRNA in the carcinogenesis whose role has been firstly unraveled in prostate cancer. Expression of this lncRNA is activated by androgen in prostate cancer cells. In addition, this lncRNA has a role in the pathogenesis intervertebral disc degeneration, myocardial ischemia-reperfusion injury, osteoarthritis, osteoporosis and Parkinson’s disease. Diagnostic role of PART1 has been assessed in some types of cancers. Moreover, dysregulation of PART1 expression is regarded as a prognostic factor in a variety of cancers. The current review provides a concise but comprehensive summary of the role of PART1 in different cancers and non-malignant disorders

Episode-like pulse testosterone supplementation induces tumor senescence and growth arrest down-modulating androgen receptor through modulation of p-ERK1/2, pAR ser81 and CDK1 signaling: biological implications for men treated with testosterone replacement therapy

Despite the growing body of knowledge showing that testosterone (T) may not significantly affect tumor progression in hypogonadal patients treated for prostate cancer (Pca), the use of this hormone in this population still remains controversial. The effects of continuous or pulsed T stimulation were tested in vitro and in vivo on androgen-sensitive Pca cell lines in order to assess the differential biological properties of these two treatment modalities. Pulsed T treatment resulted in a greater inhibition than continuous T supplementation of tumor growth in vitro and in vivo. The effects of pulsed T treatment on tumor growth inhibition, G0/G1 cell cycle arrest, and tumor senescence was more pronounced than those obtained upon continuous T treatments. Mechanistic studies revealed that G0/G1 arrest and tumor senescence upon pulsed T treatment were associated with a marked decrease in cyclin D1, c-Myc and SKp2, CDK4 and p-Rb levels and upregulation of p27 and p-ERK1/2. Pulsed, but not continuous, T supplementation decreased the expression levels of AR, p-AR ser81 and CDK1 in both cellular models. The in vitro results were confirmed in an in vivo xenografts, providing evidence of a greater inhibitory activity of pulsed supraphysiological T supplementation than continuous treatment, both in terms of tumor volume and decreased AR, p-AR ser81 , PSA and CDK1 staining. The rapid cycling from hypogonadal to physiological or supra-physiological T intraprostatic concentrations results in cytostatic and senescence effects in preclinical models of androgen-sensitive Pca. Our preclinical evidence provides relevant new insights in the biology of Pca response to pulsed T supplementation

The coregulator Alien

Alien has characteristics of a corepressor for selected members of the nuclear hormone receptor (NHR) superfamily and also for transcription factors involved in cell cycle regulation and DNA repair. Alien mediates gene silencing and represses the transactivation of specific NHRs and other transcription factors to modulate hormone response and cell proliferation. Alien is a highly conserved protein and is expressed in a wide variety of tissues. Knockout of the gene encoding Alien in mice is embryonic lethal at a very early stage, indicating an important evolutionary role in multicellular organisms. From a mechanistic perspective, the corepressor function of Alien is in part mediated by histone deacetylase (HDAC) activity. In addition, Alien seems to modulate nucleosome assembly activity. This suggests that Alien is acting on chromatin not only through recruitment of histone-modifying activities, but also through enhancing nucleosome assembly