Role of ubiquitin and the HPV E6 oncoprotein in E6AP-mediated ubiquitination

Deregulation of the ubiquitin ligase E6 associated protein (E6AP) encoded by the UBE3A gene has been associated with three different clinical pictures. Hijacking of E6AP by the E6 oncoprotein of distinct human papillomaviruses (HPV) contributes to the development of cervical cancer, whereas loss of E6AP expression or function is the cause of Angelman syndrome, a neurodevelopmental disorder, and increased expression of E6AP has been involved in autism spectrum disorders. Although these observations indicate that the activity of E6AP has to be tightly controlled, only little is known about how E6AP is regulated at the posttranslational level. Here, we provide evidence that the hydrophobic patch of ubiquitin comprising Leu-8 and Ile-44 is important for E6AP-mediated ubiquitination, whereas it does not affect the catalytic properties of the isolated catalytic HECT domain of E6AP. Furthermore, we show that the HPV E6 oncoprotein rescues the disability of full-length E6AP to use a respective hydrophobic patch mutant of ubiquitin for ubiquitination and that it stimulates E6AP-mediated ubiquitination of Ring1B, a known substrate of E6AP, in vitro and in cells. Based on these data, we propose that E6AP exists in at least two different states, an active and a less active or latent one, and that the activity of E6AP is controlled by noncovalent interactions with ubiquitin and allosteric activators such as the HPV E6 oncoprotein.

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The E6 Oncoproteins of High-Risk Papillomaviruses Bind to a Novel Putative GAP Protein, E6TP1, and Target It for Degradation

Molecular and Cellular Biology ◽

10.1128/mcb.19.1.733 ◽

1999 ◽

Vol 19 (1) ◽

pp. 733-744 ◽

Cited By ~ 138

Author(s):

Qingshen Gao ◽

Seetha Srinivasan ◽

Sarah N. Boyer ◽

David E. Wazer ◽

Vimla Band

Keyword(s):

High Risk ◽

P53 Protein ◽

Single Gene ◽

Human Papillomaviruses ◽

Dominant Negative ◽

Hpv16 E6 ◽

Hpv E6 ◽

E6 Oncoprotein ◽

E6 Protein

ABSTRACT The high-risk human papillomaviruses (HPVs) are associated with carcinomas of the cervix and other genital tumors. Previous studies have identified two viral oncoproteins, E6 and E7, which are expressed in the majority of HPV-associated carcinomas. The ability of high-risk HPV E6 protein to immortalize human mammary epithelial cells (MECs) has provided a single-gene model to study the mechanisms of E6-induced oncogenic transformation. In this system, the E6 protein targets the p53 tumor suppressor protein for degradation, and mutational analyses have shown that E6-induced degradation of p53 protein is required for MEC immortalization. However, the inability of most dominant-negative p53 mutants to induce efficient immortalization of MECs suggests the existence of additional targets of the HPV E6 oncoprotein. Using the yeast two-hybrid system, we have isolated a novel E6-binding protein. This polypeptide, designated E6TP1 (E6-targeted protein 1), exhibits high homology to GTPase-activating proteins for Rap, including SPA-1, tuberin, and Rap1GAP. The mRNA for E6TP1 is widely expressed in tissues and in vitro-cultured cell lines. The gene for E6TP1 localizes to chromosome 14q23.2-14q24.3 within a locus that has been shown to undergo loss of heterozygosity in malignant meningiomas. Importantly, E6TP1 is targeted for degradation by the high-risk but not the low-risk HPV E6 proteins both in vitro and in vivo. Furthermore, the immortalization-competent but not the immortalization-incompetent HPV16 E6 mutants target the E6TP1 protein for degradation. Our results identify a novel target for the E6 oncoprotein and provide a potential link between HPV E6 oncogenesis and alteration of a small G protein signaling pathway.

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FOXP1 syndrome: a review of the literature and practice parameters for medical assessment and monitoring

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09358-1 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Reymundo Lozano ◽

Catherine Gbekie ◽

Paige M. Siper ◽

Shubhika Srivastava ◽

Jeffrey M. Saland ◽

...

Keyword(s):

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Medical Assessment ◽

Forkhead Box ◽

Organ Systems ◽

Practice Parameters ◽

Assessment And Monitoring ◽

Multidisciplinary Group ◽

The Brain

AbstractFOXP1 syndrome is a neurodevelopmental disorder caused by mutations or deletions that disrupt the forkhead box protein 1 (FOXP1) gene, which encodes a transcription factor important for the early development of many organ systems, including the brain. Numerous clinical studies have elucidated the role of FOXP1 in neurodevelopment and have characterized a phenotype. FOXP1 syndrome is associated with intellectual disability, language deficits, autism spectrum disorder, hypotonia, and congenital anomalies, including mild dysmorphic features, and brain, cardiac, and urogenital abnormalities. Here, we present a review of human studies summarizing the clinical features of individuals with FOXP1 syndrome and enlist a multidisciplinary group of clinicians (pediatrics, genetics, psychiatry, neurology, cardiology, endocrinology, nephrology, and psychology) to provide recommendations for the assessment of FOXP1 syndrome.

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Role of molecular biomarker human papilloma virus (HPV) E6 oncoprotein in cervical cancer screening

Gynecologic Oncology ◽

10.1016/j.ygyno.2020.06.496 ◽

2020 ◽

Vol 158 (3) ◽

pp. 590-596

Author(s):

Rifat Ara ◽

Sabera Khatun ◽

Shahana Pervin ◽

Munira Jahan ◽

Umme Shahera ◽

...

Keyword(s):

Cervical Cancer ◽

Cancer Screening ◽

Human Papilloma Virus ◽

Cervical Cancer Screening ◽

Molecular Biomarker ◽

Papilloma Virus ◽

Hpv E6 ◽

E6 Oncoprotein

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Microglial ASD-related genes are involved in oligodendrocyte differentiation

Scientific Reports ◽

10.1038/s41598-021-97257-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Yuta Takanezawa ◽

Shogo Tanabe ◽

Daiki Kato ◽

Rie Ozeki ◽

Masayo Komoda ◽

...

Keyword(s):

Autism Spectrum ◽

Oligodendrocyte Precursor Cells ◽

Oligodendrocyte Differentiation ◽

Spectrum Disorders ◽

Oligodendrocyte Precursor ◽

Oligodendrocyte Development ◽

Igf1 Expression ◽

Phagocytosis Activity

AbstractAutism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNA-binding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc2). Although these ASD-related genes are detected in glial cells such as microglia, the effect of Chd8 or Tsc2 deficiency on microglial functions and microglia-mediated brain development remains unclear. In this study, we investigated the role of microglial Chd8 and Tsc2 in cytokine expression, phagocytosis activity, and neuro/gliogenesis from neural stem cells (NSCs) in vitro. Chd8 or Tsc2 knockdown in microglia reduced insulin-like growth factor-1(Igf1) expression under lipopolysaccharide (LPS) stimulation. In addition, phagocytosis activity was inhibited by Tsc2 deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd8 or Tsc2 deficiency. These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD.

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Yoga

Handbook of Research on Evidence-Based Perspectives on the Psychophysiology of Yoga and Its Applications - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-7998-3254-6.ch021 ◽

2021 ◽

pp. 361-390

Author(s):

Kankan Gulati ◽

Praerna H. Bhargav ◽

Shalu Elizabeth Abraham ◽

Hemant Bhargav

Keyword(s):

Autism Spectrum Disorder ◽

Psychological Distress ◽

Neurodevelopmental Disorder ◽

Well Being ◽

Autism Spectrum ◽

Relaxation Techniques ◽

Yoga Therapy ◽

Gross Motor Skills

Autism spectrum disorder (ASD), a neurodevelopmental disorder, manifests as impairment in social communication an interaction with restrictive and repetitive patterns of behaviour. Yoga therapy, a mind-body intervention, employs a multi-dimensional approach to reduce psychological distress and bring balance and harmony at the levels of body, breath and mind through physical postures, breathing practices, chanting, and relaxation techniques, respectively, thus enhancing overall well-being. Various yoga studies have shown promise in improving symptoms of ASD by improvement in sensory processing, gross motor skills, balance and coordination, cognition, imitation skills, and the ability to connect in relationships. This chapter aims to provide an overview of the potential role of Yoga therapy in the management of ASDs with emphasis on future standardized yoga trials with robust methodology and long-term follow-ups to establish the clinical utility of Yoga therapy for the same. Also, a tentative yoga lifestyle module for ASD with necessary contra-indications and practical tips has been provided.

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Role of Oligodendrocytes and Myelin in the Pathophysiology of Autism Spectrum Disorder

Brain Sciences ◽

10.3390/brainsci10120951 ◽

2020 ◽

Vol 10 (12) ◽

pp. 951

Author(s):

Alma Y. Galvez-Contreras ◽

David Zarate-Lopez ◽

Ana L. Torres-Chavez ◽

Oscar Gonzalez-Perez

Keyword(s):

Autism Spectrum Disorder ◽

Interpersonal Communication ◽

Neurodevelopmental Disorder ◽

Brain Regions ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Spectrum Disorder ◽

Abnormal Development ◽

Matter Production

Autism Spectrum Disorder (ASD) is an early neurodevelopmental disorder that involves deficits in interpersonal communication, social interaction, and repetitive behaviors. Although ASD pathophysiology is still uncertain, alterations in the abnormal development of the frontal lobe, limbic areas, and putamen generate an imbalance between inhibition and excitation of neuronal activity. Interestingly, recent findings suggest that a disruption in neuronal connectivity is associated with neural alterations in white matter production and myelination in diverse brain regions of patients with ASD. This review is aimed to summarize the most recent evidence that supports the notion that abnormalities in the oligodendrocyte generation and axonal myelination in specific brain regions are involved in the pathophysiology of ASD. Fundamental molecular mediators of these pathological processes are also examined. Determining the role of alterations in oligodendrogenesis and myelination is a fundamental step to understand the pathophysiology of ASD and identify possible therapeutic targets.

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Pathogenetical and Neurophysiological Features of Patients with Autism Spectrum Disorder: Phenomena and Diagnoses

Journal of Clinical Medicine ◽

10.3390/jcm8101588 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1588

Author(s):

Yunho Jin ◽

Jeonghyun Choi ◽

Seunghoon Lee ◽

Jong Won Kim ◽

Yonggeun Hong

Keyword(s):

Autism Spectrum Disorder ◽

Neural Development ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Social Deficits ◽

Restricted Interests ◽

Neuropsychiatric Comorbidities ◽

The Brain

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is accompanied by social deficits, repetitive and restricted interests, and altered brain development. The majority of ASD patients suffer not only from ASD itself but also from its neuropsychiatric comorbidities. Alterations in brain structure, synaptic development, and misregulation of neuroinflammation are considered risk factors for ASD and neuropsychiatric comorbidities. Electroencephalography has been developed to quantitatively explore effects of these neuronal changes of the brain in ASD. The pineal neurohormone melatonin is able to contribute to neural development. Also, this hormone has an inflammation-regulatory role and acts as a circadian key regulator to normalize sleep. These functions of melatonin may play crucial roles in the alleviation of ASD and its neuropsychiatric comorbidities. In this context, this article focuses on the presumable role of melatonin and suggests that this hormone could be a therapeutic agent for ASD and its related neuropsychiatric disorders.

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Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Genetics in Medicine ◽

10.1038/s41436-021-01152-7 ◽

2021 ◽

Author(s):

Felix Marbach ◽

◽

Georgi Stoyanov ◽

Florian Erger ◽

Constantine A. Stratakis ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Global Developmental Delay ◽

Missense Variants ◽

Large Patient ◽

Significant Enrichment

Abstract Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

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Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.592868 ◽

2021 ◽

Vol 8 ◽

Author(s):

Natália Lourenço de Freitas ◽

Maria Gabriela Deberaldini ◽

Diana Gomes ◽

Aline Renata Pavan ◽

Ângela Sousa ◽

...

Keyword(s):

Cervical Cancer ◽

Histone Deacetylases ◽

Histone Deacetylase Inhibitors ◽

Hdac Inhibitors ◽

Human Papillomaviruses ◽

Therapeutic Interventions ◽

Cellular Targets

The role of epigenetic modifications on the carcinogenesis process has received a lot of attention in the last years. Among those, histone acetylation is a process regulated by histone deacetylases (HDAC) and histone acetyltransferases (HAT), and it plays an important role in epigenetic regulation, allowing the control of the gene expression. HDAC inhibitors (HDACi) induce cancer cell cycle arrest, differentiation, and cell death and reduce angiogenesis and other cellular events. Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses. They are major human carcinogens, being intricately linked to the development of cancer in 4.5% of the patients diagnosed with cancer worldwide. Long-term infection of high-risk (HR) HPV types, mainly HPV16 and HPV18, is one of the major risk factors responsible for promoting cervical cancer development. In vitro and in vivo assays have demonstrated that HDACi could be a promising therapy to HPV-related cervical cancer. Regardless of some controversial studies, the therapy with HDACi could target several cellular targets which HR-HPV oncoproteins could be able to deregulate. This review article describes the role of HDACi as a possible intervention in cervical cancer treatment induced by HPV, highlighting the main advances reached in the last years and providing insights for further investigations regarding those agents against cervical cancer.

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Expression Analysis of Ermin and Listerin E3 Ubiquitin Protein Ligase 1 Genes in Autistic Patients

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.701977 ◽

2021 ◽

Vol 14 ◽

Author(s):

Shadi Shiva ◽

Jalal Gharesouran ◽

Hani Sabaie ◽

Mohammad Reza Asadi ◽

Shahram Arsang-Jang ◽

...

Keyword(s):

Translational Regulation ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Verbal Interactions ◽

Ubiquitin Protein Ligase ◽

Genes Expression ◽

Exact Etiology ◽

And Gender ◽

Study Participants

Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder that involves social interaction defects, impairment of non-verbal and verbal interactions, and limited interests along with stereotypic activities. Its incidence has been increasing rapidly in recent decades. Despite numerous attempts to understand the pathophysiology of ASD, its exact etiology is still unclear. Recent data shows the role of accurate myelination and translational regulation in ASD’s pathogenesis. In this study, we assessed Ermin (ERMN) and Listerin E3 Ubiquitin Protein Ligase 1 (LTN1) genes expression in Iranian ASD patients and age- and gender-matched healthy subjects’ peripheral blood using quantitative real-time PCR to recognize any probable dysregulation in the expression of these genes and propose this disorder’s mechanisms. Analysis of the expression demonstrated a significant ERMN downregulation in total ASD patients compared to the healthy individuals (posterior beta = −0.794, adjusted P-value = 0.025). LTN1 expression was suggestively higher in ASD patients in comparison with the corresponding control individuals. Considering the gender of study participants, the analysis showed that the mentioned genes’ different expression levels were significant only in male subjects. Besides, a significant correlation was found between expression of the mentioned genes (r = −0.49, P < 0.0001). The present study provides further supports for the contribution of ERMN and LTN1 in ASD’s pathogenesis.

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