Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital myotonic dystrophy type 1 (CDM1) affects patients from birth and is associated with mental retardation and impaired muscle development. CDM1 patients carry 1000-3000 CTG repeats in the DMPK gene and display defective skeletal muscles differentiation, resulting in reduced size of myotubes and decreased number of satellite cells. In this study, human myoblasts in culture deriving from control and DM1 embryos (3200 CTG repeats) were analyzed using both a biochemical and electron microscopic approach, in order to provide new insights into the molecular mechanisms underlying such alteration. Interestingly, electron microscopy analysis showed not only ultrastructural features of abnormal differentiation but also revealed the presence of autophagic vacuoles in DM1 myoblasts not undergoing differentiation. In accordance with the electron microscopic findings, the autophagic markers LC3 and ATG5, but not apoptotic markers, were significantly up regulated in DM1 myoblasts after differentiating medium addition. The induction of autophagic processes in DM1 myoblasts was concomitant to p53 over-expression and inhibition of the mTOR-S6K1 pathway, causatively involved in autophagy. Moreover biochemical alterations of the two main signal transduction pathways involved in differentiation were observed in DM1 myoblasts, in particular decreased activation of p38MAPK and persistent activation of the MEK-ERK pathway. This work, while demonstrating that major signaling pathways regulating myoblasts differentiation are profoundly deranged in DM1 myoblasts, for the first time provides evidence of autophagy induction, possibly mediated by p53 activation in response to metabolic stress which might contribute to the dystrophic alterations observed in the muscles of congenital DM1 patients.
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PMID:Altered signal transduction pathways and induction of autophagy in human myotonic dystrophy type 1 myoblasts. 2079 47

Diabetes is increasingly becoming a major cause of large-scale morbidity and mortality. Diabetes-induced oxidative stress alters numerous intracellular signaling pathways. Although testicular dysfunction is a major concern in diabetic men, the mechanistic alterations in the testes that lead to hypogonadism are not yet clear. Oxidative mitochondrial DNA damage, as indicated by 7,8-dihydro-8-oxo-2'-deoxyguanosine, and phosphorylation of p53 at ser315 residue (p-p53ser315) increased in a stage- and cell-specific manner in the testes of rats that were diabetic for 1 month (DM1). Prolongation of diabetes for 3 months (DM3) led to an increase in nuclear oxidative DNA damage in conjunction with a decrease in the expression of p-p53ser315. The nuclei of pachytene and preleptotene spermatocytes, steps 1, 11, and 12 spermatids, secondary spermatocytes and the Sertoli cells, and the meiotic figures showed an increase in the expression of p-p53ser315. An increase in the expression of a downstream target of p53 and protein 21(cyclin-dependent kinase interacting protein 1/wild-type p53-activated factor 1) (p21(CIP1/Waf1)) in both diabetic groups did not show any time-dependent effects but occurred concurrent with an upregulation of p-p53ser315 in DM1 and a downregulation of the protein in DM3. In diabetic groups, the expression of p21(CIP1/Waf1) was mainly cytoplasmic but also perinuclear in pachytene spermatocytes and round spermatids. The cytoplasmic localization of p21(CIP1/Waf1) may be suggestive of an antiapoptotic role for the protein. The perinuclear localization is probably related to the cell cycle arrest meant for DNA damage repair. Diabetes upregulates p21(CIP1/Waf1) signaling in testicular germ cells in association with alteration in p-p53ser315 expression, probably to counteract DNA damage-induced cell death.
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PMID:Diabetes-induced oxidative DNA damage alters p53-p21CIP1/Waf1 signaling in the rat testis. 2482 39

HER2 is a trans-membrane receptor tyrosine kinase that activates multiple growth-promoting signaling pathways including PI3K-AKT and Ras-MAPK. Dysregulation of HER2 is a frequent occurrence in breast cancer that is associated with poor patient outcomes. A primary function of HER2 is suppressing apoptosis to enhance cell survival giving rise to uncontrolled proliferation and tumor growth. There has been much investigation into the mechanisms by which apoptosis is suppressed by HER2 in hopes of finding clinical targets for HER2-positive breast cancers as these cancers often become resistant to therapies that directly target HER2. Several apoptotic mechanisms have been shown to be deregulated in HER2-overexpressing cells with examples in both the intrinsic and extrinsic apoptotic pathways. HER2-mediated activation of PI3K-AKT signaling is required for many of the mechanisms HER2 uses to suppress apoptosis. HER2 overexpression is correlated with increases in anti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-xL, and Mcl-1. HER2 also suppresses p53-mediated apoptosis by upregulation of MDM2 by activation of AKT. In addition, survivin expression is often increased with HER2 overexpression leading to inhibition of caspase activation. There is also recent evidence to suggest HER2 can directly influence apoptosis by translocation to the mitochondria to inhibit cytochrome c release. HER2 can also suppress cellular reaction to death ligands, especially TRAIL-induced apoptosis. Elucidation of the mechanisms of apoptotic suppression by HER2 suggest that clinical treatment will likely need to target multiple components of these pathways as there is redundancy in HER2-mediated cell survival. Several therapies have attempted to target Bcl-2 proteins that have promising pre-clinical results. Next-generation HER2 targeting therapies include irreversible pan-ERBB inhibitors and antibody-drug conjugates, such as T-DM1 that has very promising clinical results thus far. Further investigation should include elucidating mechanisms of resistance to HER2-targeted therapies and targeting of multiple components of HER2-mediated cell survival.
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PMID:Regulation of Apoptosis by HER2 in Breast Cancer. 2708 47

Myotonic dystrophy type 1 (DM1) is a multi-systemic disorder caused by abnormally expanded stretches of CTG DNA triplets in the DMPK gene, leading to mutated-transcript RNA-toxicity. MicroRNAs (miRNAs) are short non-coding RNAs that, after maturation, are loaded onto the RISC effector complex that destabilizes target mRNAs and represses their translation. In DM1 muscle biopsies not only the expression, but also the intracellular localization of specific miRNAs is disrupted, leading to the dysregulation of the relevant mRNA targets. To investigate the functional alterations of the miRNA/target interactions in DM1, we analyzed by RNA-sequencing the RISC-associated RNAs in skeletal muscle biopsies derived from DM1 patients and matched controls. The mRNAs found deregulated in DM1 biopsies were involved in pathways and functions relevant for the disease, such as energetic metabolism, calcium signaling, muscle contraction and p53-dependent apoptosis. Bioinformatic analysis of the miRNA/mRNA interactions based on the RISC enrichment profiles, identified 24 miRNA/mRNA correlations. Following validation in 21 independent samples, we focused on the couple miR-29c/ASB2 because of the role of miR-29c in fibrosis (a feature of late-stage DM1 patients) and of ASB2 in the regulation of muscle mass. Luciferase reporter assay confirmed the direct interaction between miR-29c and ASB2. Moreover, decreased miR-29c and increased ASB2 levels were verified also in immortalized myogenic cells and primary fibroblasts, derived from biopsies of DM1 patients and controls. CRISPR/Cas9-mediated deletion of CTG expansions rescued normal miR-29c and ASB2 levels, indicating a direct link between the mutant repeats and the miRNA/target expression. In conclusion, functionally relevant miRNA/mRNA interactions were identified in skeletal muscles of DM1 patients, highlighting the dysfunction of miR-29c and ASB2.
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PMID:High-throughput analysis of the RNA-induced silencing complex in myotonic dystrophy type 1 patients identifies the dysregulation of miR-29c and its target ASB2. 2995 39