MicroRNAs as regulators of death receptors signaling

Garofalo, Michela; Condorelli, Gerolama; Croce, Carlo M.

doi:10.1038/cdd.2009.105

Cited by 104 publications

(70 citation statements)

References 50 publications

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“…MiRNAs are a class of non-coding RNAs that regulate post-transcriptional gene expressions and silence target mRNAs. MiRNAs have been established to act as anti-apoptotic or pro-apoptotic regulators by targeting different mRNAs involved in the apoptotic pathways, especially BCL-2 family proteins (Garofalo et al, 2010;Chen et al, 2014). For example, miR-15/16 targets the antiapoptotic factor (Bcl-2) and the loss or reduced expression of the tumor suppressor of miR-15/16 may elucidate the elevation of Bcl-2 level in some tumors (Cimmino et al, 2005;Allegra et al, 2014).…”

Section: Role Of Apoptosis In Cancermentioning

confidence: 99%

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Goldar¹,

Khaniani²,

Derakhshan³

et al. 2015

Asian Pacific Journal of Cancer Prevention

462

338

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Programmed cell death (PCD) or apoptosis is a mechanism which is crucial for all multicellular organisms to control cell proliferation and maintain tissue homeostasis as well as eliminate harmful or unnecessary cells from an organism. Defects in the physiological mechanisms of apoptosis may contribute to different human diseases like cancer. Identification of the mechanisms of apoptosis and its effector proteins as well as the genes responsible for apoptosis has provided a new opportunity to discover and develop novel agents that can increase the sensitivity of cancer cells to undergo apoptosis or reset their apoptotic threshold. These novel targeted therapies include those targeting anti-apoptotic Bcl-2 family members, p53, the extrinsic pathway, FLICE-inhibitory protein (c-FLIP), inhibitor of apoptosis (IAP) proteins, and the caspases. In recent years a number of these novel agents have been assessed in preclinical and clinical trials. In this review, we introduce some of the key regulatory molecules that control the apoptotic pathways, extrinsic and intrinsic death receptors, discuss how defects in apoptotic pathways contribute to cancer, and list several agents being developed to target apoptosis.

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Section: Role Of Apoptosis In Cancermentioning

confidence: 99%

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Goldar¹,

Khaniani²,

Derakhshan³

et al. 2015

Asian Pacific Journal of Cancer Prevention

462

338

View full text Add to dashboard Cite

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“…9 Among them, the microRNA-34 family mimics p53 biological effects by inducing cell cycle arrest and apoptosis in response to DNA damage. 10,11 Here we studied epithelial cell apoptosis, TP53 and miR-34a expression in skin and gut biopsies in non-transplanted FA patients, and FA patients with aGVHD of different grades.…”

Section: Introductionmentioning

confidence: 99%

Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Wang

Romero

Ratajczak

et al. 2012

Bone Marrow Transplant

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Fanconi anemia (FA) patients have an increased risk of acute GVHD (aGVHD) after hematopoietic SCT, with hypersensitivity to DNAcross-linking agents and defective DNA repair. MicroRNA-34 and p53 can induce apoptosis after DNA damage.Here we assessed epithelial cell apoptosis, and studied TP53 and miR-34a expression in the skin and gut biopsies in five non-transplanted FA patients, in 20 FA patients with aGVHD and in 25 acquired aplastic anemia patients (AA). Epithelial apoptosis was higher in FA than in acquired AA patients in both the skin and gut biopsies, though they had a similar preparative regimen. Further study on gut biopsies in FA patients showed that this deleterious effect was not linked to TP53 gene overexpression. As, among p53-independent signaling pathways of apoptosis, the microRNA-34 family mimics p53 apoptotic effects in response to DNA damage, we studied miR-34a expression in the same series of FA patients' gut biopsies. MiR-34a expression level was higher in severe aGVHD compared with non-aGVHD subjects or non-transplanted patients, and significantly related to apoptotic cell numbers across the three groups of FA patients. Thus, in FA patients, increased apoptosis occurs in target epithelial cells of severe aGVHD, and this deleterious effect is linked to overexpression of miR-34a but not TP53.

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“…While early reports indicated that miRs were sensitive markers of toxicity, and might have predictive and diagnostic value in the treatment of APAP (2,15), there have been a few studies that attempted to understand how miR alterations affect Editorial Noncoding RNAs as therapeutics for acetaminophen-induced liver injury APAP-induced liver injury. While it has been established that miRs control a number of cellular functions, the specific functions controlled by different miRs are largely still under investigation (16). Antagonism of miRs has therapeutic potential as they are targetable in a highly specific fashion, and their degradation can have profound effects on transcription of specific genes without affecting the genome.…”

Section: Micro-rnas (Mirs) In Acetaminophen-induced Liver Injurymentioning

confidence: 99%

Noncoding RNAs as therapeutics for acetaminophen-induced liver injury

Woolbright

Jaeschke

2016

Stem Cell Investig.

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Acetaminophen-induced injury and acute liver failure as a clinically relevant modelAcetaminophen-(APAP) induced acute liver failure (ALF) is a major cause of morbidity and mortality in the US (1). Currently, the major therapeutic is N-acetylcysteine (NAC), which is highly effective when given within 8 h of drug overdose. However, late-presenting patients commonly have poor outcomes, and NAC is not effective in these patients. As such, additional therapeutics are urgently needed to treat late-presenting patients. Critical to the generation of new drugs is the continued development of our understanding of APAP-induced ALF in human patients. While a number of recent papers from our group and others have made considerable advances in understanding mechanisms of toxicity in patients and human hepatocytes (2-5), there is still a lack of actionable therapeutic targets. Liver transplantation is the gold standard procedure for treating late-stage ALF but this operation is expensive and comes with additional costs of lifelong anti-rejection medication. In addition, due to limited donor organs, this therapeutic option is not always available (1). There are also ethical issues to consider as a majority of APAP-induced liver injury cases are due to attempted suicide. It is thus imperative that new modalities of treatment, including novel pharmacological agents, be explored for patients who suffer from drug-induced liver injury and acute liver failure.The mechanisms behind APAP-induced liver injury have been extensively examined over the last 40 years (6,7). APAP is typically non-toxic when taken at therapeutic dosages as it is largely metabolized through phase II metabolism by glucuronosyltransferases (glucuronidation) and sulfotransferases (sulfation), and then excreted via the urine (7).Minor levels of APAP are metabolized by cytochrome P450 2E1 (Cyp2E1), which results in the formation of the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) (7). However, when sulfation is saturated (8), additional quantities of APAP are metabolized by Cyp2E1 and NAPQI accumulation initiates liver toxicity. Excess NAPQI causes significant depletion of glutathione, protein adduct formation especially in mitochondria (9,10) and a mitochondrial oxidative and nitrosative stress (11), which is then amplified by translocation of c-Jun N-terminal kinase (JNK) to the mitochondria (12,13). This triggers the opening of the mitochondrial permeability transition pore resulting in collapse of the membrane potential, cessation of ATP formation, and matrix swelling (14). The latter effect results in the outer membrane rupture with release of mitochondrial membrane proteins including apoptosis inducing factor and endonuclease G, which translocate to the nucleus and trigger DNA fragmentation (6). The extensive mitochondrial dysfunction and karyolysis are responsible for the necrotic cell death (6). A number of therapeutics have been proposed based on these mechanisms and the pathways that control them; however, new mechanisms that complement our cu...

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MicroRNAs as regulators of death receptors signaling

Cited by 104 publications

References 50 publications

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Molecular Mechanisms of Apoptosis and Roles in Cancer Development and Treatment

Increased apoptosis is linked to severe acute GVHD in patients with Fanconi anemia

Noncoding RNAs as therapeutics for acetaminophen-induced liver injury

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