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1.
Biomed Pharmacother ; 153: 113333, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35779420

ABSTRACT

Brain and Muscle Arnt-like Protein 1 (BMAL1) is an essential component of the molecular clock underlying circadian rhythmicity. Its function has been recently associated with mood and reward processing alterations. We investigated the behavioural and neurobiological impact of Bmal1 gene deletion in mice, and how this could affect rewarding effects of cocaine. Additionally, key clock genes and components of the dopamine system were assessed in several brain areas. Our results evidence behavioural alterations in Bmal1-KO mice, including changes in locomotor activity with impaired habituation to environments, short-term memory and social recognition impairments. In addition, Bmal1-KO mice experienced reduced cocaine-induced sensitisation and rewarding effects of cocaine as well as reduced cocaine-seeking behaviour. Furthermore, Bmal1 deletion influenced the expression of other clock-related genes in the mPFC and striatum, as well as alterations in the expression of dopaminergic elements. Overall, the present article offers a novel and extensive characterisation of Bmal1-KO animals. We suggest that reduced cocaine's rewarding effects in these mutant mice might be related to Bmal1 role as an expression regulator of MAO and TH, two essential enzymes involved in dopamine metabolism.


Subject(s)
ARNTL Transcription Factors , Cocaine , Cognitive Dysfunction , ARNTL Transcription Factors/genetics , Animals , Circadian Rhythm/genetics , Cocaine/pharmacology , Dopamine , Mice , Mice, Knockout
2.
Oncogene ; 41(24): 3341-3354, 2022 06.
Article in English | MEDLINE | ID: mdl-35534539

ABSTRACT

It is known that Rho GTPases control different aspects of the biology of skin stem cells (SSCs). However, little information is available on the role of their upstream regulators under normal and tumorigenic conditions in this process. To address this issue, we have used here mouse models in which the activity of guanosine nucleotide exchange factors of the Vav subfamily has been manipulated using both gain- and loss-of-function strategies. These experiments indicate that Vav2 and Vav3 regulate the number, functional status, and responsiveness of hair follicle bulge stem cells. This is linked to gene expression programs related to the reinforcement of the identity and the quiescent state of normal SSCs. By contrast, in the case of cancer stem cells, they promote transcriptomal programs associated with the identity, activation state, and cytoskeletal remodeling. These results underscore the role of these Rho exchange factors in the regulation of normal and tumor epidermal stem cells.


Subject(s)
Proto-Oncogene Proteins c-vav , Skin , Stem Cells , Animals , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Epidermal Cells/cytology , Epidermal Cells/metabolism , Epidermis/metabolism , Hair Follicle/cytology , Hair Follicle/metabolism , Mice , Neoplastic Stem Cells/metabolism , Neoplastic Stem Cells/pathology , Proto-Oncogene Proteins c-vav/genetics , Proto-Oncogene Proteins c-vav/metabolism , Skin/cytology , Skin/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Stem Cells/cytology , Stem Cells/metabolism , rho GTP-Binding Proteins/genetics , rho GTP-Binding Proteins/metabolism
3.
NAR Genom Bioinform ; 3(2): lqab031, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33937766

ABSTRACT

Circadian-regulated genes are essential for tissue homeostasis and organismal function, and are therefore common targets of scrutiny. Detection of rhythmic genes using current analytical tools requires exhaustive sampling, a demand that is costly and raises ethical concerns, making it unfeasible in certain mammalian systems. Several non-parametric methods have been commonly used to analyze short-term (24 h) circadian data, such as JTK_cycle and MetaCycle. However, algorithm performance varies greatly depending on various biological and technical factors. Here, we present CircaN, an ad-hoc implementation of a non-linear mixed model for the identification of circadian genes in all types of omics data. Based on the variable but complementary results obtained through several biological and in silico datasets, we propose a combined approach of CircaN and non-parametric models to dramatically improve the number of circadian genes detected, without affecting accuracy. We also introduce an R package to make this approach available to the community.

4.
Nat Commun ; 11(1): 4788, 2020 09 22.
Article in English | MEDLINE | ID: mdl-32963234

ABSTRACT

Regenerative proliferation capacity and poor differentiation are histological features usually linked to poor prognosis in head and neck squamous cell carcinoma (hnSCC). However, the pathways that regulate them remain ill-characterized. Here, we show that those traits can be triggered by the RHO GTPase activator VAV2 in keratinocytes present in the skin and oral mucosa. VAV2 is also required to maintain those traits in hnSCC patient-derived cells. This function, which is both catalysis- and RHO GTPase-dependent, is mediated by c-Myc- and YAP/TAZ-dependent transcriptomal programs associated with regenerative proliferation and cell undifferentiation, respectively. High levels of VAV2 transcripts and VAV2-regulated gene signatures are both associated with poor hnSCC patient prognosis. These results unveil a druggable pathway linked to the malignancy of specific SCC subtypes.


Subject(s)
Cell Proliferation , Head and Neck Neoplasms/metabolism , Proto-Oncogene Proteins c-vav/genetics , Proto-Oncogene Proteins c-vav/metabolism , Squamous Cell Carcinoma of Head and Neck/metabolism , Animals , Cell Differentiation , Disease Models, Animal , Epidermis/metabolism , Epidermis/pathology , GTP Phosphohydrolases , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Humans , Hyperplasia/pathology , Keratinocytes/pathology , Mice , Mice, Knockout , Mucous Membrane/metabolism , Prognosis , RNA, Messenger/metabolism , Signal Transduction , Squamous Cell Carcinoma of Head and Neck/genetics , Squamous Cell Carcinoma of Head and Neck/pathology , Transcriptome
7.
Stem Cells ; 35(4): 1015-1027, 2017 04.
Article in English | MEDLINE | ID: mdl-27862634

ABSTRACT

Pw1/Peg3 is a parentally imprinted gene expressed in adult stem cells in every tissue thus far examined including the stem cells of the hair follicle. Using a Pw1/Peg3 reporter mouse, we carried out a detailed dissection of the stem cells in the bulge, which is a major stem cell compartment of the hair follicle in mammalian skin. We observed that PW1/Peg3 expression initiates upon placode formation during fetal development, coincident with the establishment of the bulge stem cells. In the adult, we observed that PW1/Peg3 expression is found in both CD34+ and CD34- populations of bulge stem cells. We demonstrate that both populations can give rise to new hair follicles, reconstitute their niche, and self-renew. These results demonstrate that PW1/Peg3 is a reliable marker of the full population of follicle stem cells and reveal a novel CD34- bulge stem-cell population. Stem Cells 2017;35:1015-1027.


Subject(s)
Antigens, CD34/metabolism , Hair Follicle/cytology , Kruppel-Like Transcription Factors/metabolism , Stem Cells/cytology , Stem Cells/metabolism , Aging/physiology , Animals , Animals, Newborn , Biomarkers/metabolism , Cell Self Renewal , Cell Separation , Gene Expression , Genes, Reporter , Mice, Inbred C57BL , Staining and Labeling , Stem Cell Niche
8.
J Cell Biol ; 212(1): 77-89, 2016 Jan 04.
Article in English | MEDLINE | ID: mdl-26711500

ABSTRACT

During development, multipotent progenitor cells establish lineage-specific programmers of gene activation and silencing underlying their differentiation into specialized cell types. We show that the Polycomb component Cbx4 serves as a critical determinant that maintains the epithelial identity in the developing epidermis by repressing nonepidermal gene expression programs. Cbx4 ablation in mice results in a marked decrease of the epidermal thickness and keratinocyte (KC) proliferation associated with activation of numerous neuronal genes and genes encoding cyclin-dependent kinase inhibitors (p16/p19 and p57). Furthermore, the chromodomain- and SUMO E3 ligase-dependent Cbx4 activities differentially regulate proliferation, differentiation, and expression of nonepidermal genes in KCs. Finally, Cbx4 expression in KCs is directly regulated by p63 transcription factor, whereas Cbx4 overexpression is capable of partially rescuing the effects of p63 ablation on epidermal development. These data demonstrate that Cbx4 plays a crucial role in the p63-regulated program of epidermal differentiation, maintaining the epithelial identity and proliferative activity in KCs via repression of the selected nonepidermal lineage and cell cycle inhibitor genes.


Subject(s)
Cell Lineage , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelium/metabolism , Polycomb Repressive Complex 1/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Cell Differentiation , Cell Proliferation , Epithelium/growth & development , Ligases , Mice , Mice, Inbred C57BL , Mice, Knockout , Polycomb Repressive Complex 1/deficiency , Polycomb Repressive Complex 1/genetics , Stem Cells/cytology , Stem Cells/metabolism , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/genetics
9.
Mol Cell Biol ; 32(8): 1442-52, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22331466

ABSTRACT

One of the most striking epigenetic alterations that occurs at the level of the nucleosome is the complete exchange of the canonical H2A histones for the macroH2A variant. Here, we provide insight into the poorly recognized function of macroH2A in transcriptional activation and demonstrate its relevance in embryonic and adult stem cells. Knockdown of macroH2A1 in mouse embryonic stem (mES) cells limited their capacity to differentiate but not their self-renewal. The loss of macroH2A1 interfered with the proper activation of differentiation genes, most of which are direct target genes of macroH2A. Additionally, macroH2A1-deficient mES cells displayed incomplete inactivation of pluripotency genes and formed defective embryoid bodies. In vivo, macroH2A1-deficient teratomas contained a massive expansion of malignant, undifferentiated carcinoma tissue. In the heterogeneous culture of primary human keratinocytes, macroH2A1 levels negatively correlated with the self-renewal capacity of the pluripotent compartment. Together these results establish macroH2A1 as a critical chromatin component that regulates the delicate balance between self-renewal and differentiation of embryonic and adult stem cells.


Subject(s)
Adult Stem Cells/cytology , Cell Differentiation/physiology , Cell Proliferation , Embryonic Stem Cells/cytology , Histones/physiology , Adult Stem Cells/physiology , Animals , Chromatin/physiology , Embryoid Bodies/metabolism , Embryoid Bodies/pathology , Embryonic Stem Cells/physiology , Humans , Keratinocytes/cytology , Keratinocytes/physiology , Mice , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/physiology , Teratoma/metabolism , Teratoma/pathology
10.
Am J Pathol ; 172(1): 156-66, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18165265

ABSTRACT

Colorectal adenocarcinoma is the second cause of cancer mortality in developed countries. Rac1 is a member of the family of Rho GTPases that regulates many intracellular signaling pathways, including those involved in tumorigenesis, invasion, and metastasis. We have investigated the role of Rac1 in colorectal tumor progression by genetic modification of the human colorectal adenocarcinoma cell line SW620 to either overexpress Rac1 or lack Rac1 expression. Tumor behavior was studied by orthotopic injection of stably modified cell lines into the cecal wall of athymic nude mice, a model that replicates the histopathological appearance and clinical behavior of human colorectal adenocarcinoma in humans. While overexpression of Rac1 resulted in an accelerated tumorigenic process, inducing a faster mortality rate, inhibition of Rac1 completely suppressed tumor formation. These results suggest that Rac1 plays a major role in colorectal adenocarcinoma progression. Finally, interference with Rac1 function may provide an important tool to block the malignant phenotype of colorectal adenocarcinoma cells.


Subject(s)
Adenocarcinoma/pathology , Colonic Neoplasms/pathology , rac1 GTP-Binding Protein/physiology , Animals , Cell Line , Disease Progression , Humans , Male , Mice , Mice, Nude , Neoplasm Metastasis , Neoplasm Transplantation , Neoplastic Processes , Signal Transduction , Time Factors , rac1 GTP-Binding Protein/metabolism
12.
Mol Carcinog ; 44(1): 60-6, 2005 Sep.
Article in English | MEDLINE | ID: mdl-15924349

ABSTRACT

During epidermal chemical carcinogenesis benign papillomas convert to squamous cell carcinomas, some of which undergo epithelial-mesenchymal conversion to highly malignant spindle cell tumors. TGFbeta inhibits early stages of carcinogenesis but promotes the spindle cell phenotype in later stages. One hallmark of spindle cell tumors is upregulation of the alpha 5 beta 1 integrin fibronectin receptor. To examine the significance of altered alpha 5 beta1 integrin expression, we induced tumors in transgenic mice expressing alpha 5 beta1 in the suprabasal epidermal layers. Invalpha 5 beta1 mice developed threefold more papillomas and squamous cell carcinomas than wild-type (Wt) littermates; however, no spindle cell tumors or increased metastases were observed. Suprabasal expression of the alpha 6 beta 4 integrin increases squamous cell carcinoma formation and decreases TGFbeta sensitivity while alpha 3 beta1 may have the opposite effect. In contrast, nuclear phosphoSmad2 labeling in Invalpha 5 beta1 epidermis and tumors was indistinguishable from Wt, and suprabasal alpha 5 beta1 did not block TGFbeta-induced Smad2/3 translocation or growth inhibition in cultured keratinocytes. We conclude that upregulation of alpha 5 beta1 does not predispose the epidermis to undergo conversion to spindle cell tumors and that the mechanism by which alpha 5 beta1 influences susceptibility to carcinogenesis is independent of perturbed TGFbeta signaling.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Transformation, Neoplastic/pathology , Gene Expression Regulation, Neoplastic , Integrin alpha5beta1/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Animals , DNA-Binding Proteins/metabolism , Integrin alpha5beta1/genetics , Mice , Mice, Transgenic , Phosphorylation , Protein Transport , Smad2 Protein , Smad3 Protein , Trans-Activators/metabolism
13.
Bioessays ; 27(6): 602-13, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15892119

ABSTRACT

Rho proteins belong to the small GTPases superfamily. They function as molecular switches that, in response to diverse stimuli, control key signaling and structural aspects of the cell. Although early studies proposed a role for Rho GTPases in cellular transformation, this effect was underestimated due to the fact that no genetic mutations affecting Rho-encoding genes were found in tumors. Recently, it has become evident that Rho GTPases participate in the carcinogenic process by either overexpression of some of the members of the family with oncogenic activity, downmodulation of other members with suggested tumor suppressor activity, or by alteration of upstream modulators or downstream effectors. Thus, alteration of the levels of expression of different members of the family of Rho GTPases has been detected in many types of human tumors leading to a great interest in the cellular effects elicited by these oncoproteins. This essay reviews the current evidence of dysregulation of Rho signaling by overexpression in human tumors.


Subject(s)
Cell Transformation, Neoplastic/metabolism , Gene Expression Regulation, Enzymologic , Gene Expression Regulation, Neoplastic , Neoplasms/enzymology , rho GTP-Binding Proteins/genetics , rho GTP-Binding Proteins/metabolism , Animals , Cell Transformation, Neoplastic/genetics , Humans , Neoplasms/genetics , Signal Transduction , rho GTP-Binding Proteins/classification
14.
Biochim Biophys Acta ; 1705(2): 121-32, 2004 Dec 17.
Article in English | MEDLINE | ID: mdl-15588766

ABSTRACT

The high incidence of overexpression of some members of the Rho family of GTPases in human tumors suggests that (1) these proteins are involved in cancer onset, and (2) they are potential candidates for a therapeutic intervention. In recent years, the characterization of downstream effectors to Rho GTPases has provided crucial clues on the general cellular effects that permit aberrant proliferation and adhesiveness of tumor cells. The activation of many of these effector proteins in turn results in the modulation of the activity of several transcription factors that play an important role at various levels of Rho signaling. The precise mechanisms by which Rho GTPases participate in carcinogenesis are still not fully understood. However, it is becoming more evident that the specific role of Rho overexpression in tumor initiation, progression and metastasis, as well as the nature and cause of such overexpression in specific human tumors (i.e., transient or stable; tumor environment-regulated; genetic or epigenetic) may be linked to the activation of specific signaling pathways that result in transcriptional regulation. In this review, we summarize the functions of Rho proteins in the regulation of several transcription factors and their relationship to tumor biology.


Subject(s)
Gene Expression Regulation, Neoplastic , Neoplasms/enzymology , rho GTP-Binding Proteins/physiology , Cell Transformation, Neoplastic , Humans , Neoplasm Invasiveness , Neoplasm Metastasis , Signal Transduction , Transcription Factors/metabolism
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