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Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression.

ABSTRACT: ARF suppresses aberrant cell growth upon c-Myc overexpression by activating p53 responses. Nevertheless, the precise mechanism by which ARF specifically restrains the oncogenic potential of c-Myc without affecting its normal physiological function is not well understood. Here, we show that low levels of c-Myc expression stimulate cell proliferation, whereas high levels inhibit by activating the ARF/p53 response. Although the mRNA levels of ARF are induced in both scenarios, the accumulation of ARF protein occurs only when ULF-mediated degradation of ARF is inhibited by c-Myc overexpression. Moreover, the levels of ARF are reduced through ULF-mediated ubiquitination upon DNA damage. Blocking ARF degradation by c-Myc overexpression dramatically stimulates the apoptotic responses. Our study reveals that ARF stability control is crucial for differentiating normal (low) versus oncogenic (high) levels of c-Myc expression and suggests that differential effects on ULF- mediated ARF ubiquitination by c-Myc levels act as a barrier in oncogene-induced stress responses.

SUBMITTER: Chen D

PROVIDER: S-EPMC3841012 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression.

Chen Delin D Kon Ning N Zhong Jiayun J Zhang Pingzhao P Yu Long L Gu Wei W

Molecular cell 20130606 1

ARF suppresses aberrant cell growth upon c-Myc overexpression by activating p53 responses. Nevertheless, the precise mechanism by which ARF specifically restrains the oncogenic potential of c-Myc without affecting its normal physiological function is not well understood. Here, we show that low levels of c-Myc expression stimulate cell proliferation, whereas high levels inhibit by activating the ARF/p53 response. Although the mRNA levels of ARF are induced in both scenarios, the accumulation of A ...[more]

PMID: 23747016

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Project description:Allogeneic hematopoietic stem cell transplantation is a curative treatment for numerous hematological malignancies. However, acute graft-versus-host disease (aGvHD) is a major complication affecting 40-70% of all transplant patients, whereby the earliest and most frequent presentation is in the skin. MicroRNAs play a role in varied biological process and have been reported as potential biomarkers for aGvHD. More recently, microRNAs have received added attention as circulatory biomarkers that can be detected in biofluids. In this study, we performed global microRNA expression profiling using a discovery cohort of diagnostic cutaneous aGvHD biopsies (n?=?5, stages 1-3) and healthy volunteers (n?=?4), in order to identify a signature list of microRNAs that could be used as diagnostic biomarkers for cutaneous aGvHD. Candidate microRNAs (n?=?8) were then further investigated in a validation cohort of post-HSCT skin biopsies (n?=?17), pre-HSCT skin biopsies (n?=?6) and normal controls (n?=?6) for their association with aGvHD. Expression of let-7c (p?=?0.014), miR-503-5p (p?=?0.003), miR-365a-3p (p?=?0.02), miR-34a-5p (p?<?0.001) and miR-34a-3p (p?=?0.006) were significantly differentially expressed between groups and significantly associated with survival outcome in post-HSCT patients (miR-503-5p ROC AUC?=?0.83 p?=?0.021, Log Rank p?=?0.003; miR-34a-3p ROC AUC?=?0.93, p?=?0.003, Log Rank p?=?0.004). There was no association with relapse. A statistical interaction between miR-34a-3p and miR-503-5p (p?=?0.016) was diagnostic for aGvHD. Expression levels of the miR-34a-5p protein target p53 were assessed in the epidermis of the skin, and an inverse correlation was identified (r2?=?0.44, p?=?0.039). Expression of the validated candidate microRNAs was also assessed at day 28 post-HSCT in the sera of transplant recipients, in order to investigate their potential as circulatory microRNA biomarkers. Expression of miR-503-5p (p?=?0.001), miR-34a-5p (p?=?0.005), and miR-34a-3p (p?=?0.004) was significantly elevated in the sera of patients who developed aGvHD versus no-aGvHD (n?=?30) and miR-503-5p was associated with overall survival (OS) (ROC AUC?=?0.80, p?=?0.04, Log Rank p?=?0.041). In conclusion, this investigation reports that microRNA expression levels in clinical skin biopsies, obtained at the time of cutaneous aGvHD onset, show potential as diagnostic biomarkers for aGvHD and as predictive biomarkers for OS. In addition, the same microRNAs can be detected in the circulation and show predictive association with post-HSCT outcomes.

Project description:Adiponectin exerts beneficial effects by reducing inflammation and improving lipid metabolism and insulin sensitivity. Although the adiponectin level is lower in obese individuals, whether weight gain reduces adiponectin expression in humans is controversial. We sought to investigate the role of weight gain, and consequent changes in leptin, on altering adiponectin expression in humans.Forty-four normal-weight healthy subjects were recruited (mean age 29 years; 14 women) and randomized to either gain 5% of body weight by 8 weeks of overfeeding (n=34) or maintain weight (n=10). Modest weight gain of 3.8±1.2?kg resulted in increased adiponectin level (P=0.03), whereas weight maintenance resulted in no changes in adiponectin. Further, changes in adiponectin correlated positively with changes in leptin (P=0.0085). In-vitro experiments using differentiated human white preadipocytes showed that leptin increased adiponectin mRNA and protein expression, whereas a leptin antagonist had opposite effects. To understand the role of leptin in established obesity, we compared adipose tissue samples obtained from normal-weight versus obese subjects. We noted, first, that leptin activated cellular signaling pathways and increased adiponectin mRNA in the adipose tissue from normal-weight participants, but did not do so in the adipose tissue from obese participants. Second, we noted that obese subjects had increased caveolin-1 expression, which attenuates leptin-dependent increases in adiponectin.Modest weight gain in healthy individuals is associated with increases in adiponectin levels, which correlate positively with changes in leptin. In vitro, leptin induces adiponectin expression, which is attenuated by increased caveolin-1 expression. In addition, the adipose tissue from obese subjects shows increased caveolin-1 expression and impaired leptin signaling. This leptin signal impairment may prevent concordant increases in adiponectin levels in obese subjects despite their high levels of leptin. Therefore, impaired leptin signaling may contribute to low adiponectin expression in obesity and may provide a target for increasing adiponectin expression, hence improving insulin sensitivity and cardio-metabolic profile in obesity.

Dataset Information

Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression.

Publications

Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression.

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