Marta I. Gallego

Instituto de Salud Carlos III

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Pedro A. Lazo

Consejo Superior de Investigaciones Científicas

Lothar Hennighausen

National Institutes of Health

Rodolfo Murillas

Centro de Investigación Biomédica en Red

Sara Ballester

Instituto de Salud Carlos III

Gertraud W. Robinson

National Institute of Diabetes and Digestive and Kidney Diseases

Alicia Ballester

Unidad Funcional de Investigación de Enfermedades Crónicas

Enrique Recuero

Research Institute Hospital 12 de Octubre

Raquel Pérez-Tavárez

Instituto de Química Física Blas Cabrera

A Sigen

University College Dublin

Diana de Prado-Verdún

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

Cooperative Institutions

Instituto de Salud Carlos III

Universidad Autónoma de Madrid

Consejo Superior de Investigaciones Científicas

Research Institute Hospital 12 de Octubre

Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas

National Institutes of Health

Universidad Complutense de Madrid

Unidad Funcional de Investigación de Enfermedades Crónicas

Centro Nacional de Microbiologia

Centro de Investigación Biomédica en Red de Cáncer

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Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action

Blood (2006)

Renhai Cao Meit A. Björndahl Marta I. Gallego Shaohua Chen Piotr Religa

Lymphangiogenesis

Lymphatic vessel

Lymphatic Endothelium

10.1182/blood-2005-06-2538

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Citations (182)

Deletion in Human Chromosome Region 12q13-15 by Integration of Human Papillomavirus DNA in a Cervical Carcinoma Cell Line

Journal of Biological Chemistry (1995)

Marta I. Gallego Pedro A. Lazo

In human cervical carcinomas papillomavirus DNA is frequently integrated in the cell genome. We have cloned the integration site of human papillomavirus-18 DNA in human chromosome region 12q13-15 present in the SW756 cervical carcinoma cell line. Viral DNA is broken from nucleotides 2643 to 3418 in the E1 and E2 open reading frames, resulting in a deletion of 775 bases of viral DNA. Cloning and sequence analysis of the rearranged and germline alleles shows that there is no homology between the target cellular and viral DNA, suggesting it is a nonhomologous recombination. The target cellular region is called papillomavirus associated locus 2 (PAL2). The 5′- and 3′-flanking probes derived from the hybrid viral-cellular clone detect completely different germline restriction fragments in DNA from cells with normal chromosome 12. There is no overlap between the restriction maps of the target germline clones obtained with 5′- and 3′-flanking probes. Probes from these germline clones beyond the breakpoint position do not detect any DNA rearrangement in SW756 cells DNA. These data prove that there is a deletion of cellular DNA as consequence of the integration, with an estimated minimum size of 14 kilobases. Both cellular flanking probes are outside the amplicon of this chromosome region identified in the OSA and RMS13 sarcoma cell lines, comprising SAS-CHOP-CDK4-MDM2 genes and where translocation breakpoints are located in liposarcomas. The integration at 12q13-15 might have been selected by its contribution to the tumor phenotype. In human cervical carcinomas papillomavirus DNA is frequently integrated in the cell genome. We have cloned the integration site of human papillomavirus-18 DNA in human chromosome region 12q13-15 present in the SW756 cervical carcinoma cell line. Viral DNA is broken from nucleotides 2643 to 3418 in the E1 and E2 open reading frames, resulting in a deletion of 775 bases of viral DNA. Cloning and sequence analysis of the rearranged and germline alleles shows that there is no homology between the target cellular and viral DNA, suggesting it is a nonhomologous recombination. The target cellular region is called papillomavirus associated locus 2 (PAL2). The 5′- and 3′-flanking probes derived from the hybrid viral-cellular clone detect completely different germline restriction fragments in DNA from cells with normal chromosome 12. There is no overlap between the restriction maps of the target germline clones obtained with 5′- and 3′-flanking probes. Probes from these germline clones beyond the breakpoint position do not detect any DNA rearrangement in SW756 cells DNA. These data prove that there is a deletion of cellular DNA as consequence of the integration, with an estimated minimum size of 14 kilobases. Both cellular flanking probes are outside the amplicon of this chromosome region identified in the OSA and RMS13 sarcoma cell lines, comprising SAS-CHOP-CDK4-MDM2 genes and where translocation breakpoints are located in liposarcomas. The integration at 12q13-15 might have been selected by its contribution to the tumor phenotype.

Restriction map

10.1074/jbc.270.41.24321

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Citations (80)

Functional rescue of Stat5a-null mammary tissue through the activation of compensating signals including Stat5b.

PubMed (1998)

Xinke Liu Marta I. Gallego Gilbert H. Smith Gertraud W. Robinson Lothar Hennighausen

Prolactin induces mammopoiesis and lactogenesis through the Janus kinase-signal transducers and activators of transcription pathway, with Stat5a being a principal and obligate cytoplasmic and nuclear signaling molecule. Mice from which the Stat5a gene has been deleted fail to develop functional mammary tissue during their first pregnancy. Lobuloalveolar outgrowth is curtailed, and epithelial cells fail to progress to functional differentiation. Here, we investigate whether the effect of Stat5a deficiency is restricted to the epithelium and whether the gland has the capacity to activate alternative signaling pathways that could restore development and function. Mammary gland transplant experiments showed that Stat5a-deficient epithelium does not differentiate in wild-type stroma, thus demonstrating a cell-autonomous role for Stat5a. The capacity of Stat5a-deficient mammary tissue to develop and secrete milk was measured after consecutive pregnancies and with postpartum suckling. Neither of these regimens could independently restore lactation. However, the combination of several pregnancies and suckling stimuli resulted in a partial establishment of lactation and an increase of Stat5b activity. These experiments demonstrate that the mammary gland has inherent plasticity that allows it to use different signals to achieve its ultimate purpose, the production of milk to nurture newborn offspring.

Hippo signaling pathway

STAT5

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Citations (74)

Targeted expression of HGF/SF in mouse mammary epithelium leads to metastatic adenosquamous carcinomas through the activation of multiple signal transduction pathways

Oncogene (2003)

Marta I. Gallego Brian Bierie Lothar Hennighausen

10.1038/sj.onc.1207063

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Citations (99)

Complex genomic rearrangement within the 12q15 multiple aberration region induced by integrated human papillomavirus 18 in a cervical carcinoma cell line

Molecular Carcinogenesis (1997)

Marta I. Gallego Eric Schoenmakers Wim J.M. Van de Ven Pedro A. Lazo

Human papillomavirus (HPV) DNA is integrated into the host genome in cervical cancer. The cervical carcinoma cell line SW756 has integrated HPV-18 DNA in chromosome region 12q15, in the papillomavirus-associated locus-2 (PAL2). By polymerase chain reaction and hybridization of an arrayed cosmid library with oligonucleotides from the rearranged allele, we determined the pre-integration germline structure of the region. PAL2 was located approximately 10 kb from sequence-tagged site marker U27131, which was the marker most proximal to the 3' flank of the integrated viral DNA. HPV-18 DNA integration induced a complex genomic rearrangement resulting in inversion and deletion of cellular sequences. PAL2 is within the multiple aberration region, which has been shown to be affected in several types of benign tumors of mesenchymal origin. The integrated viral DNA was located 50 kb from a CpG island and 150 kb upstream of the high-mobility group I-C (HMGI-C) gene. The HMGI-C gene and the integrated HPV-18 DNA had opposite transcriptional orientations. No overexpression or altered message of the HMGI-C gene was detected in three cervical carcinoma cell lines. The integrated viral DNA did not affect any other known gene in the region and may be a marker for an unknown gene associated with malignant tumor phenotypes.

CpG site

genomic DNA

10.1002/(sici)1098-2744(199707)19:2<114::aid-mc6>3.0.co;2-f

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Citations (19)

Nonviral CRISPR/Cas9 mutagenesis for streamlined generation of mouse lung cancer models

Proceedings of the National Academy of Sciences (2024)

Irene Lara‐Sáez Ángeles Mencía Enrique Recuero Yinghao Li Marta García

Functional analysis in mouse models is necessary to establish the involvement of a set of genetic variations in tumor development. A modeling platform to facilitate and cost-effectively analyze the role of multiple genes in carcinogenesis would be valuable. Here, we present an innovative strategy for lung mutagenesis using CRISPR/Cas9 ribonucleoproteins delivered via cationic polymers. This approach allows the simultaneous inactivation of multiple genes. We validate the effectiveness of this system by targeting a group of tumor suppressor genes, specifically Rb1 , Rbl1 , Pten , and Trp53 , which were chosen for their potential to cause lung tumors, namely small cell lung carcinoma (SCLC). Tumors with histologic and transcriptomic features of human SCLC emerged after intratracheal administration of CRISPR/polymer nanoparticles. These tumors carried loss-of-function mutations in all four tumor suppressor genes at the targeted positions. These findings were reproduced in two different pure genetic backgrounds. We provide a proof of principle for simplified modeling of lung tumorigenesis to facilitate functional testing of potential cancer-related genes.

10.1073/pnas.2322917121

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Citations (1)

The human zinc‐finger protein‐7 gene is located 90 kb 3′ of MYC and is not expressed in Burkitt lymphoma cell lines

International Journal of Cancer (1994)

Marta I. Gallego Pedro A. Lazo

Abstract The zinc‐finger gene‐7 (ZNFT) was located 90 kb 3′ of MYC on human chromosome 8 band q24 by pulsed‐field gel electropho‐resis (PFGE). This position lies between the MLV14 and BVRI loci, 2 variant translocation breakpoints in Burkrtt tymphomas. The structure of the ZNF7 gene was not altered by translocations in Burkitt‐lymphoma cell lines as shown by its germline‐restriction map configuration. The chromosomal region surrounding the ZNF7 gene was extensively methylated. The ZNF7 gene was not expressed in 19 BL cell lines. Expression was detected only in the BL41 and BL47 cell lines and in the SW756 cervical‐carcinoma cell line. The UNA in each was of a different size. We postulate that the lack of ZNF7 expression in Burkitt lymphomas might contribute to the tumor phenotype.

Breakpoint

10.1002/ijc.2910580618

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Citations (8)

Genetic alterations by human papillomaviruses in oncogenesis

FEBS Letters (1992)

Pedro A. Lazo Marta I. Gallego Sara Ballester Elena Feduchi

The integration sites in the cellular genome of human papillomavirus are located in chromosomal regions always associated with oncogenes or other known tumor phenotypes. Two regions, 8q24 and 12q13, are common to several cases of cervical carcinoma and can have integrated more than one type of papillomavirus DNA. These two chromosomal regions contain several genes implicated in oncogenesis. These observations strongly imply that viral integration sites of DNA tumor viruses can be used as the access point to chromosomal regions where genes implicated in the tumor phenotype are located, a situation similar to that of non‐transforming retroviruses.

Chromosomal region

Oncovirus

10.1016/0014-5793(92)80175-g

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Citations (28)

Low Levels of Amyloid Precursor Protein (APP) Promote Neurogenesis and Decrease Gliogenesis in Human Neural Stem Cells

International Journal of Molecular Sciences (2023)

Raquel Coronel Victoria López-Alonso Marta I. Gallego Isabel Liste

Amyloid precursor protein (APP) has been widely studied due to its association with Alzheimer's disease (AD). However, the physiological functions of APP are still largely unexplored. APP is a transmembrane glycoprotein whose expression in humans is abundant in the central nervous system. Specifically, several studies have revealed the high expression of APP during brain development. Previous studies in our laboratory revealed that a transient increase in APP expression induces early cell cycle exit of human neural stem cells (hNSCs) and directs their differentiation towards glial cells (gliogenesis) while decreasing their differentiation towards neurons (neurogenesis). In the present study, we have evaluated the intrinsic cellular effects of APP down-expression (using siRNA) on cell death, cell proliferation, and cell fate specification of hNSCs. Our data indicate that APP silencing causes cellular effects opposite to those obtained in previous APP overexpression assays, inducing cell proliferation in hNS1 cells (a model line of hNSCs) and favoring neurogenesis instead of gliogenesis in these cells. In addition, we have analyzed the gene and protein expression levels of β-Catenin as a possible molecule involved in these cellular effects. These data could help to understand the biological role of APP, which is necessary to deepen the knowledge of AD.

Gliogenesis

Synaptogenesis

Precursor cell

Neurosphere

10.3390/ijms241914635

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Restrained Th17 response and myeloid cell infiltration into the central nervous system by human decidua-derived mesenchymal stem cells during experimental autoimmune encephalomyelitis

Stem Cell Research & Therapy (2016)

Beatriz Bravo Marta I. Gallego Ana I. Flores Rafael Bornstein Alba Puente-Bedia

Abstract Background Multiple sclerosis is a widespread inflammatory demyelinating disease. Several immunomodulatory therapies are available, including interferon-β, glatiramer acetate, natalizumab, fingolimod, and mitoxantrone. Although useful to delay disease progression, they do not provide a definitive cure and are associated with some undesirable side-effects. Accordingly, the search for new therapeutic methods constitutes an active investigation field. The use of mesenchymal stem cells (MSCs) to modify the disease course is currently the subject of intense interest. Decidua-derived MSCs (DMSCs) are a cell population obtained from human placental extraembryonic membranes able to differentiate into the three germ layers. This study explores the therapeutic potential of DMSCs. Methods We used the experimental autoimmune encephalomyelitis (EAE) animal model to evaluate the effect of DMSCs on clinical signs of the disease and on the presence of inflammatory infiltrates in the central nervous system. We also compared the inflammatory profile of spleen T cells from DMSC-treated mice with that of EAE control animals, and the influence of DMSCs on the in vitro definition of the Th17 phenotype. Furthermore, we analyzed the effects on the presence of some critical cell types in central nervous system infiltrates. Results Preventive intraperitoneal injection of DMSCs resulted in a significant delay of external signs of EAE. In addition, treatment of animals already presenting with moderate symptoms resulted in mild EAE with reduced disease scores. Besides decreased inflammatory infiltration, diminished percentages of CD4 + IL17 + , CD11b + Ly6G + and CD11b + Ly6C + cells were found in infiltrates of treated animals. Early immune response was mitigated, with spleen cells of DMSC-treated mice displaying low proliferative response to antigen, decreased production of interleukin (IL)-17, and increased production of the anti-inflammatory cytokines IL-4 and IL-10. Moreover, lower RORγT and higher GATA-3 expression levels were detected in DMSC-treated mice. DMSCs also showed a detrimental influence on the in vitro definition of the Th17 phenotype. Conclusions DMSCs modulated the clinical course of EAE, modified the frequency and cell composition of the central nervous system infiltrates during the disease, and mediated an impairment of Th17 phenotype establishment in favor of the Th2 subtype. These results suggest that DMSCs might provide a new cell-based therapy for the control of multiple sclerosis.

Natalizumab

Encephalomyelitis

10.1186/s13287-016-0304-5

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Citations (40)