Publications by authors named "Valeria Serra"

19 Publications

  • Page 1 of 1

COR758, a negative allosteric modulator of GABA receptors.

Neuropharmacology 2021 Mar 30;189:108537. Epub 2021 Mar 30.

Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, Italy; Guy Everett Laboratory, University of Cagliari, 09042, Monserrato, Italy; Center of Excellence "Neurobiology of Addiction", University of Cagliari, 09042, Monserrato, Italy. Electronic address:

Allosteric modulators of G protein coupled receptors (GPCRs), including GABARs (GABARs), are promising therapeutic candidates. While several positive allosteric modulators (PAM) of GABARs have been characterized, only recently the first negative allosteric modulator (NAM) has been described. In the present study, we report the characterization of COR758, which acts as GABAR NAM in rat cortical membranes and CHO cells stably expressing GABARs (CHO-GABA). COR758 failed to displace the antagonist [H]CGP54626 from the orthosteric binding site of GABARs showing that it acts through an allosteric binding site. Docking studies revealed a possible new allosteric binding site for COR758 in the intrahelical pocket of the GABA monomer. COR758 inhibited basal and GABAR-stimulated O-(3-[Sthio)-triphosphate ([S]GTPγS) binding in brain membranes and blocked the enhancement of GABAR-stimulated [S]GTPγS binding by the PAM GS39783. Bioluminescent resonance energy transfer (BRET) measurements in CHO-GABA cells showed that COR758 inhibited G protein activation by GABA and altered GABAR subunit rearrangements. Additionally, the compound altered GABAR-mediated signaling such as baclofen-induced inhibition of cAMP production in transfected HEK293 cells, agonist-induced Ca mobilization as well as baclofen and the ago-PAM CGP7930 induced phosphorylation of extracellular signal-regulated kinases (ERK1/2) in CHO-GABA cells. COR758 also prevented baclofen-induced outward currents recorded from rat dopamine neurons, substantiating its property as a NAM for GABARs. Altogether, these data indicate that COR758 inhibits G protein signaling by GABARs, likely by interacting with an allosteric binding-site. Therefore, COR758 might serve as a scaffold to develop additional NAMs for therapeutic intervention.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108537DOI Listing
March 2021

Prenatal THC Does Not Affect Female Mesolimbic Dopaminergic System in Preadolescent Rats.

Int J Mol Sci 2021 Feb 7;22(4). Epub 2021 Feb 7.

Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, 09042 Monserrato, Italy.

Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure.
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http://dx.doi.org/10.3390/ijms22041666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914408PMC
February 2021

Mesolimbic dopamine dysregulation as a signature of information processing deficits imposed by prenatal THC exposure.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Mar 6;105:110128. Epub 2020 Oct 6.

Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy. Electronic address:

Cannabis is the illicit drug most widely used by pregnant women worldwide. Its growing acceptance and legalization have markedly increased the risks of child psychopathology, including psychotic-like experiences, which lowers the age of onset for a first psychotic episode. As the majority of patients with schizophrenia go through a premorbid condition long before this occurs, understanding neurobiological underpinnings of the prodromal stage of the disease is critical to improving illness trajectories and therapeutic outcomes. We have previously shown that male rat offspring prenatally exposed to Δ-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area (VTA), converging on a hyperdopaminergic state. This leads to a silent psychotic-like endophenotype that is unmasked by a single exposure to THC. Here, we further characterized the VTA dopamine neuron and sensorimotor gating functions of PCE rats exposed to acute stress or a challenge of the D2 receptor agonist apomorphine, by using in vivo single-unit extracellular recordings and Prepulse Inhibition (PPI) analyses. At pre-puberty, PCE male rat offspring display a reduced population activity of VTA dopamine neurons in vivo, the majority of which are tonically active. PCE male progeny also exhibit enhanced sensitivity to dopamine D2 (DAD2) receptor activation and a vulnerability to acute stress, which is associated with compromised sensorimotor gating functions. This data extends our knowledge of the multifaceted sequelae imposed by PCE in the mesolimbic dopamine system of male pre-adolescent rats, which renders a neural substrate highly susceptible to subsequent challenges that may trigger psychotic-like outcomes.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110128DOI Listing
March 2021

Mobile Health in Adherence to Oral Anticancer Drugs: A Scoping Review.

Comput Inform Nurs 2020 Jun 19;39(1):17-23. Epub 2020 Jun 19.

Author Affiliations: Department of Health Professions (DAPS), University Hospital "Policlinico Umberto I" (Ms Gambalunga); IRCCS "Regina Elena" National Cancer Institute (Dr Iacorossi and Ms Serra); Centre of Excellence for Nursing Scholarship OPI Rome Italy (Dr Notarnicola); and Research Unit Nursing Science, Campus Bio-Medico of Rome University (Drs Piredda and De Marinis), Rome, Italy.

In oncology, adherence to oral antineoplastic medication is a key element of treatment, on which the success of any therapeutic intervention depends. Given their widespread use in clinical practice, it is important to identify tools that can facilitate the monitoring and self-management of the patient at home, to avoid the consequences of employing ineffective treatment. One of the tools available today to take action on this phenomenon is mobile health technology. The aim of this review is to describe published studies relating to the use of mobile health to promote adherence to oral antineoplastic medication. This scoping review was conducted using the framework proposed by Arksey and O'Malley, adapted according to Levac et al. Of 1320 articles identified, only seven met the eligibility criteria and therefore were included in the review. All seven articles involved the use of digital means to measure adherence to treatment, patient satisfaction, acceptability and feasibility of the digital means used, and presence of symptoms, but not the effectiveness of the digital instrument used. In conclusion, the use of digital means to assist adherence of cancer patients to oral antineoplastic medication is widely recognized, but its effectiveness in clinical practice is poorly supported by the nature of the published studies.
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http://dx.doi.org/10.1097/CIN.0000000000000643DOI Listing
June 2020

Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone.

Nat Neurosci 2019 12 14;22(12):1975-1985. Epub 2019 Oct 14.

Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria, Monserrato, Italy.

The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how cannabis exposure affects the maturation of this neuromodulatory system remains limited. Here, we show that male, but not female, offspring of Δ-tetrahydrocannabinol (THC)-exposed dams, a rat PCE model, exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area, including altered excitatory-to-inhibitory balance and switched polarity of long-term synaptic plasticity. The resulting hyperdopaminergic state leads to increased behavioral sensitivity to acute THC exposure during pre-adolescence. The neurosteroid pregnenolone, a US Food and Drug Administration (FDA) approved drug, rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, thus suggesting a therapeutic approach for offspring exposed to cannabis during pregnancy.
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http://dx.doi.org/10.1038/s41593-019-0512-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884689PMC
December 2019

Dysfunctional mesocortical dopamine circuit at pre-adolescence is associated to aggressive behavior in MAO-A hypomorphic mice exposed to early life stress.

Neuropharmacology 2019 11 6;159:107517. Epub 2019 Feb 6.

Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042, Monserrato, Italy; National Institute of Neuroscience (INN), Italy. Electronic address:

Aggressive behavior (AB) is a multifaceted disorder based on the interaction between genetic and environmental factors whose underlying mechanisms remain elusive. The best-characterized gene by environment (GxE) interaction for AB is the relationship between child neglect/abuse and low-activity alleles of the monoamine-oxidase A (MAOA) gene. MAOA oxidizes monoamines like serotonin and dopamine, whose aberrant signaling at discrete developmental ages plays a pivotal role in the ontogeny of AB. Here, we investigated the impact of this GxE on dopamine function at pre-adolescence by exposing hypomorphic MAOA (MAO) mice to early life stress (ES) and by performing behavioral and ex vivo electrophysiological analyses in the ventral tegmental area (VTA) and the prefrontal cortex (PFC). MAOA ES mouse dopamine neurons exhibited an enhanced post-synaptic responsiveness to excitatory inputs, aberrant plasticity in the PFC, and an AB. Systemic administration of the selective antagonist at dopamine D1 receptors SCH23390 fully restored PFC function and rescued AB. Collectively, these findings reveal that dysfunctional mesocortical dopamine signaling at pre-adolescence ties to AB in the MAOA ES mouse, and identify dopamine D1 receptor as a molecular target to be exploited for an age-tailored therapy. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.
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http://dx.doi.org/10.1016/j.neuropharm.2019.01.032DOI Listing
November 2019

Qualitative study of patients with metastatic prostate cancer to adherence of hormone therapy.

Eur J Oncol Nurs 2019 Feb 12;38:8-12. Epub 2018 Nov 12.

Division of Medical Oncology 1, IRCCS "Regina Elena" National Cancer Institute, Via Elio Chianesi, 53, 00144, Rome, Italy. Electronic address:

Purpose: To explore adherence to oral hormone treatment in patients with metastatic prostate cancer (mCRPC) and to identify the factors that influence it.

Methods: A qualitative exploratory study was conducted at the National Cancer Institute of Rome. Patients aged >18 years with castration-resistant prostate cancer (mCRPC) and who were using oral hormone drugs were recruited. Semi-structured interviews were used for data collection, subsequently transcribed verbatim and analysed using Ritchie and Spencer's framework analysis.

Results: The sample included 13 patients with a median age of 72 who were treated, on average, for seven months with abiraterone acetate (AA) (76.9%) and enzalutamide (ENZ) (23.1%). Five themes were identified: expression of the concept of adherence, favouring factors, obstacle factors, functional strategies and levels of adherence.

Conclusions: The patients express a good level of adherence, which they define in different ways-the helping relationship with the attending physician, the support of the family members and the few side effects of the drugs. For the future, it is recommended to perform a multicentre mixed method study to explain the levels of adherence and distress in women with breast cancer.
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http://dx.doi.org/10.1016/j.ejon.2018.11.004DOI Listing
February 2019

Changes in stress-stimulated allopregnanolone levels induced by neonatal estradiol treatment are associated with enhanced dopamine release in adult female rats: reversal by progesterone administration.

Psychopharmacology (Berl) 2017 Mar 24;234(5):749-760. Epub 2016 Dec 24.

Neuroscience Institute, National Research Council of Italy (CNR), Cittadella Universitaria, Monserrato, 09042, Cagliari, Italy.

Background: Allopregnanolone plays a role in the stress response and homeostasis. Alterations in the estrogen milieu during the perinatal period influence brain development in a manner that persists into adulthood. Accordingly, we showed that a single administration of estradiol benzoate (EB) on the day of birth decreases brain allopregnanolone concentrations in adult female rats.

Objective: We examined whether the persistent decrease in allopregnanolone concentrations, induced by neonatal EB treatment, might affect sensitivity to stress during adulthood.

Methods: Female rats were treated with 10 μg of EB or vehicle on the day of birth. During adulthood, the response to acute foot shock stress was assessed by measuring changes in brain allopregnanolone and corticosterone levels, as well as extracellular dopamine output in the medial prefrontal cortex (mPFC).

Results: Neonatal EB treatment enhanced stress-stimulated allopregnanolone levels in the hypothalamus, as well as extracellular dopamine output in the mPFC; this latest effect is reverted by subchronic progesterone treatment. By contrast, neonatal EB treatment did not alter stress-induced corticosterone levels, sensitivity to hypothalamic-pituitary-adrenal (HPA) axis negative feedback, or abundance of glucocorticoid and mineralocorticoid receptors.

Conclusions: The persistent decrease in brain allopregnanolone concentrations, induced by neonatal EB treatment, enhances stress-stimulated allopregnanolone levels and extracellular dopamine output during adulthood. These effects are not associated to an impairment in HPA axis activity. Heightened sensitivity to stress is a risk factor for several neuropsychiatric disorders; these results suggest that exposure to estrogen during development may predispose individuals to such disorders.
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http://dx.doi.org/10.1007/s00213-016-4511-7DOI Listing
March 2017

OTX2 regulates the expression of TAp63 leading to macular and cochlear neuroepithelium development.

Aging (Albany NY) 2015 Nov;7(11):928-36

Biochemistry Laboratory, IDI-IRCCS-FLMM, c/o Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", 00133 Rome, Italy.

OTX proteins, homologs of the Drosophila orthodenticle (Otd), are important for the morphogenesis of the neuroectoderm, and for the central nervous system formation. OTX1 and OTX2 are important for the cochlea and macula development, indeed when OTX1 is knocked down, these organs undergo developmental failure. Moreover OTX2 transfection revert this effect in OTX1(-/-) mice. The TA isoform of TP63, involved in Notch regulation pathway, has a critical function in the cochlear neuroepithelium differentiation. TAp63 positively regulates Hes5 and Atoh1 transcription. This pathway has been also demonstrated in p63(-/-) mice, and in patients p63 mutated, affected by Ectodermal Dysplasia (ED, OMIM 129810). These patients are affected by mild sensorineural deafness, most likely related to the mutation in p63 gene impairing the Notch pathway. We demonstrated the role of OTX2 on TAp63 regulation necessary for the correct formation of macular neuroepithelium and we confirmed the impairment of vestibular function caused by p63 mutations. Although the abnormalities found in our patient were still at a subclinical extent, aging could exacerbate this impairment and cause a decrease in quality of life.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694063PMC
http://dx.doi.org/10.18632/aging.100839DOI Listing
November 2015

The E3 ligase Itch knockout mice show hyperproliferation and wound healing alteration.

FEBS J 2015 Dec 12;282(23):4435-49. Epub 2015 Oct 12.

Department of Experimental Medicine and Surgery, University of 'Tor Vergata', Rome, Italy.

The HECT-type E3 ubiquitin ligase Itch is absent in the non-agouti-lethal 18H or Itchy mice, which develop a severe immunological disease. Several of the known Itch substrates are relevant for epidermal development and homeostasis, such as p63, Notch, c-Jun and JunB. By analysing Itchy mice before the onset of immunological alterations, we investigated the contribution of Itch in skin development and wound healing. Itchy newborn mice manifested hyperplastic epidermis, which is not present in adulthood. Itch(-/-) cultured keratinocytes showed overexpression of proliferating markers and increased capability to proliferate, migrate and to repair a scratch injury in vitro. These data correlated with improved in vivo wound healing in Itchy mice, at late time points of the repair process when Itch is physiologically upregulated. Despite healing acceleration, epidermal remodelling was delayed in the scars of Itch(-/-) mice, as indicated by enhanced epidermal thickening, keratinocyte proliferation and keratin 6 expression, and retarded keratin 14 polarization to the basal layer. Itch(-/-) keratinocyte prolonged activation was not associated with increased immune cell persistence in the scars. Our in vitro and in vivo results indicate that Itch plays a role in epidermal homeostasis and remodelling and this feature does not seem to depend on immunological alterations.
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http://dx.doi.org/10.1111/febs.13514DOI Listing
December 2015

Role of p63 and the Notch pathway in cochlea development and sensorineural deafness.

Proc Natl Acad Sci U S A 2013 Apr 15;110(18):7300-5. Epub 2013 Apr 15.

Biochemistry Laboratory Istituto Dermopatico Dell'Immacolata, c/o Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, 00133 Rome, Italy.

The ectodermal dysplasias are a group of inherited autosomal dominant syndromes associated with heterozygous mutations in the Tumor Protein p63 (TRP63) gene. Here we show that, in addition to their epidermal pathology, a proportion of these patients have distinct levels of deafness. Accordingly, p63 null mouse embryos show marked cochlea abnormalities, and the transactivating isoform of p63 (TAp63) protein is normally found in the organ of Corti. TAp63 transactivates hairy and enhancer of split 5 (Hes5) and atonal homolog 1 (Atoh1), components of the Notch pathway, known to be involved in cochlear neuroepithelial development. Strikingly, p63 null mice show morphological defects of the organ of Corti, with supernumerary hair cells, as also reported for Hes5 null mice. This phenotype is related to loss of a differentiation property of TAp63 and not to loss of its proapoptotic function, because cochleas in mice lacking the critical Bcl-2 homology domain (BH-3) inducers of p53- and p63-mediated apoptosis--Puma, Noxa, or both--are normal. Collectively, these data demonstrate that TAp63, acting via the Notch pathway, is crucial for the development of the organ of Corti, providing a molecular explanation for the sensorineural deafness in ectodermal dysplasia patients with TRP63 mutations.
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http://dx.doi.org/10.1073/pnas.1214498110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645580PMC
April 2013

Exogenous nef induces proinflammatory signaling events in murine macrophages.

Viral Immunol 2012 Apr 13;25(2):117-30. Epub 2012 Mar 13.

Department of Biology, University Roma Tre, Rome, Italy.

Despite the fact that murine cells are not permissive for human immunodeficiency virus type 1 (HIV-1) infection, several investigators have constructed transgenic (Tg) mice to model HIV-1-induced diseases to overcome this restriction. The generation of Tg mice expressing selected HIV-1 genes revealed that Nef harbors a major disease determinant. HIV-1 Nef protein is a molecular adapter able to interact with several cellular partners, interfering with cellular functions. The phenotype of Nef Tg mice was extensively characterized regarding in vivo development of AIDS-like disease and the effects of Nef expression in T lymphocytes, but the functions eventually corrupted by Nef in monocytes and macrophages were less studied. Nef treatment of human monocyte-derived macrophages induces the internalization of the protein and modulates the production and secretion of different chemokines and cytokines by activating specific intracellular signaling pathways (i.e., NF-κB, MAPK, and IRF3). Therefore we set up an in vitro murine macrophage-based model using stabilized cell lines and primary peritoneal macrophages, and treated them with recombinant myristoylated Nef(SF2) (recNef). Like human cells, murine macrophages responded to Nef treatment, activating IKK-α and IKK-β, JNK, and p38 MAP kinases. Activation of the NF-κB pathway is mandatory for the synthesis and release of a pool of cytokines and chemokines, including IFN-β, that induce tyrosine phosphorylation of the signal transducer and activator of transcription (STAT)-1, STAT-2, and STAT-3, in an autocrine and paracrine manner, confirming that murine macrophages respond to Nef similarly to human ones. These data extend the results previously obtained in human primary macrophages, allowing the use of murine cells in culture to study signaling events modulated by Nef in myeloid-derived cells. In particular, it may be feasible to use macrophages derived from mice knocked out in specific signaling intermediates to obtain greater insight into the mechanism of Nef-induced effects.
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http://dx.doi.org/10.1089/vim.2011.0082DOI Listing
April 2012

Functional characterization of a novel TP63 mutation in a family with overlapping features of Rapp-Hodgkin/AEC/ADULT syndromes.

Am J Med Genet A 2011 Dec 8;155A(12):3104-9. Epub 2011 Nov 8.

IDI-IRCCS Biochemistry Laboratory, c/o Department of Experimental Medicine, University of Tor Vergata, Rome, Italy.

Heterozygous mutations in TP63 cause a wide spectrum of autosomal dominant developmental disorders variably affecting skin, limbs, and face. TP63 encodes p63, a protein expressed in two main isoforms (Tap63 and ΔNp63) with critical roles in both cell differentiation and development. Some analyses suggest a relationship of the mutation site to the observed clinical picture, although this link is inconsistent. This suggests an appreciable phenotypic continuity within the TP63-related disorders. We report a 3-month-old boy ascertained for congenital scalp erosion and mild features of ectodermal dysplasia. His mother showed full-blown characteristics of Rapp-Hodgkin syndrome plus intense abdominal and popliteal freckling. Molecular investigation identified the novel TP63 mutation c.1697delG. We used a luciferase reporter assay to compare the effects on the p63 transactivation (TA) activity of c.1697delG with that of the p.Arg280Cys and p.Gln634X mutations, associated with ectrodactyly-ectodermal dysplasia-cleft lip/palate syndrome and isolated split hand/foot malformation, respectively. These results demonstrated complex behavior of c.1697delG in the TA of genes involved in epidermal differentiation and development and shed further light in the physiopathology of TP63-related disorders.
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http://dx.doi.org/10.1002/ajmg.a.34335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306552PMC
December 2011

Differential altered stability and transcriptional activity of ΔNp63 mutants in distinct ectodermal dysplasias.

J Cell Sci 2011 Jul 7;124(Pt 13):2200-7. Epub 2011 Jun 7.

Medical Research Council, Leicester University, Leicester LE19HN, UK.

Heterozygous mutations of p63, a key transcription factor in epithelial development, are causative in a variety of human ectodermal dysplasia disorders. Although the mutation spectrum of these disorders displays a striking genotype-phenotype association, the molecular basis for this association is only superficially known. Here, we characterize the transcriptional activity and protein stability of ΔNp63 mutants (that is, mutants of a p63 isoform that lacks the N-terminal transactivation domain) that are found in ectrodactyly-ectodermal dysplasia-cleft syndrome (EEC), ankyloblepharon-ectodermal dysplasia-clefting syndrome (AEC) and nonsyndromic split-hand/split-foot malformation (SHFM). DNA-binding and sterile alpha motif (SAM) domain mutants accumulate in the skin of EEC and AEC syndrome patients, respectively, and show extended half lives in vitro. By contrast, C-terminal mutations found in SHFM patients have half-lives similar to that of the wild-type protein. The increased half-life of EEC and AEC mutant proteins was reverted by overexpression of wild-type ΔNp63. Interestingly, the mutant proteins exhibit normal binding to and degradation by the E3 ubiquitin ligase Itch. Finally, EEC and AEC mutant proteins have reduced transcriptional activity on several skin-specific gene promoters, whereas SHFM mutant proteins are transcriptionally active. Our results, therefore, provide evidence for a regulatory feedback mechanism for p63 that links transcriptional activity to regulation of protein homeostasis by an unknown mechanism. Disruption of this regulatory mechanism might contribute to the pathology of p63-related developmental disorders.
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http://dx.doi.org/10.1242/jcs.079327DOI Listing
July 2011

The mammary gland and the homeobox gene Otx1.

Breast J 2010 Sep-Oct;16 Suppl 1:S53-6

Department of Experimental and Clinical Biomedical Sciences, University of Insubria, Varese, Italy.

The mammary gland, the unique organ that primarily form at puberty, is an ideal model to study the functions of homeobox (HB) genes in both development and tumorigenesis. HB genes comprise a large family of developmental regulators that have a critical role in cell growth and differentiation. In the normal mammary gland, homeobox genes are involved in ductal formation, epithelial branching, and lobulo-alveolar development by regulating epithelial proliferation and differentiation. The HB genes are controlled in a spatial and temporal manner in both stromal and epithelial cells. They are coordinately regulated by hormones and extracellular matrix, suggesting that many signaling pathways are involved in homeobox gene functions. When homeobox genes are misexpressed in animal models, different defects are displayed in mammary gland development. Aberrant expression of homeobox genes, overexpressed or downregulated, is found in primary carcinomas and in breast cancer. The Otx1 HB gene is a classic regulatory of nervous system development during embryogenesis. Postnatally Otx1 is transcribed in the anterior pituitary gland, where activates transcription of the pituitary hormones, and plays a role in hematopoiesis, enhancing pluripotent cells, and erythroid differentiation. Otx1 can still be detected in mature cells of the erythroid and megacaryocytic lineage. During cyclical development of mammary gland, the Otx1 gene is overexpressed in lactation, confirming a role of this transcription factor in cell differentiation. Recent studies report that Otx1 is overexpressed in breast cancer. Otx1 is expressed during embryogenesis, and it is expressed again during carcinogenesis, implying its possible function in differentiation of neoplastic cells.
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http://dx.doi.org/10.1111/j.1524-4741.2010.01006.xDOI Listing
February 2011

Connexin 26 (GJB2) mutations as a cause of the KID syndrome with hearing loss.

Biochem Biophys Res Commun 2010 Apr 20;395(1):25-30. Epub 2010 Mar 20.

Biochemistry Laboratory, IDI-IRCCS, C/O Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, 00133 Rome, Italy.

KID syndrome (MIM 148210) is an ectodermal dysplasia characterized by the occurrence of localized erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. KID syndrome is inherited as an autosomic dominant disease, due to mutations in the gene encoding gap junction protein GJB2 (connexin 26, Cx26). Cx26 is a component of gap junction channels in the epidermis and in the stria vascularis of the cochlea. These channels play a role in the coordinated exchange of molecules and ions occurring in a wide spectrum of cellular activities. In this paper we describe two patients with Cx26 mutations cause cell death by the alteration of protein trafficking, membrane localization and probably interfering with intracellular ion concentrations. We discuss the pathogenesis of both the hearing and skin phenotypes.
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http://dx.doi.org/10.1016/j.bbrc.2010.03.098DOI Listing
April 2010

Connexin 26 (GJB2) mutations, causing KID Syndrome, are associated with cell death due to calcium gating deregulation.

Biochem Biophys Res Commun 2010 Apr 15;394(4):909-14. Epub 2010 Mar 15.

Biochemistry Laboratory, IDI-IRCCS, C/O Department of Experimental Medicine and Biochemical Sciences, University of Rome Tor Vergata, via Montpellier 1, 00133 Rome, Italy.

The autosomic dominant KID Syndrome (MIM 148210), due to mutations in GJB2 (connexin 26, Cx26), is an ectodermal dysplasia with erythematous scaly skin lesions, keratitis and severe bilateral sensorineural deafness. The Cx26 protein is a component of gap junction channels in epithelia, including the cochlea, which coordinates the exchange of molecules and ions. Here, we demonstrate that different Cx26 mutants (Cx26D50N and Cx26G11E) cause cell death in vitro by the alteration of intra-cellular calcium concentrations. These results help to explain the pathogenesis of both the hearing and skin phenotypes, since calcium is also a potent regulator of the epidermal differentiation process.
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http://dx.doi.org/10.1016/j.bbrc.2010.03.073DOI Listing
April 2010

Knuckle pads, in an epidermal palmoplantar keratoderma patient with Keratin 9 R163W transgrediens expression.

Eur J Dermatol 2009 Mar-Apr;19(2):114-8. Epub 2008 Dec 23.

IDI-IRCCS Biochemistry laboratory c/o Dep. of Experimental Medicine, University of Tor Vergata, Via Montpellier, 1. 00133 Rome, Italy.

Epidermolytic PalmoPlantar keratoderma (EPPK) Vörner-type is an autosomal dominantly inherited skin disease, characterized by severe thickening of the palms and soles, caused by mutations in the keratin K9 (KRT9) gene. To date, a number of KRT9 mutations have been detected, most of which affect the highly conserved 1A region of the central alpha-helical domain, important for keratin heterodimerization. The most common mutation is the substitution of the arginine in position 163 with a tryptophan (R163W), which has been reported in North American, European, and Japanese populations. In a small number of cases, EPPK is associated with knuckle pad keratosis, but no correlation between this additional phenotype and a specific mutation has been found. Moreover, K9 is not normally expressed in knuckle skin, raising the question of the pathogenic mechanism leading to this additional phenotype. Here we show that in a family affected by EPPK and knuckle pad keratosis, carrying the R163W substitution, wild type (wt) and mutated K9 are strongly expressed in knuckle pads. These results suggest that the knuckle pad phenotype is due to ectopical expression of K9.
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http://dx.doi.org/10.1684/ejd.2008.0575DOI Listing
May 2009