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Papers by Antonio Di Cristofano

Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tu... more Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, includ- ing multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have

Nucleic Acids Research, 1992

ERV9 is a low repeated family of human endogenous retroviral elements whose expression is mainly ... more ERV9 is a low repeated family of human endogenous retroviral elements whose expression is mainly detectable in undifferentiated embryonal carcinoma NT2/D1 cells. In this report we have analyzed the minimal promoter region located within the ERV9 LTR. Using the transient CAT expression assay we have identified the minimal promoter region, which includes sequences spanning from -70 to + 6 relative to the major transcription start site. Deletion analysis, primer extension mapping of the transcription start sites and DNA-protein interactions assays have allowed us to define two important regions within the ERV9 minimal promoter. One region located between -70 to -39 acts as a transcriptional activating sequence and contains an Spl binding site. The second region from -7 to + 6, which resembles an initiator element (Inr), was necessary for the correct transcription start site utilization, and binds to a regulatory protein. Crosscompetition experiments using various Inr elements have indicated that the protein that binds to the ERV9 lnr element can be competed by the HIV-1 and TdT Inr sequences.

Molecular and Cellular Neuroscience, 2002

PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and me... more PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and mental deficiencies. We have used PTEN ؉/؊ mice to assess PTEN's role in subventricular zone (SVZ) precursor cells. For cultured SVZ neurosphere cells, haploinsufficiency for PTEN increases phosphorylation of Akt and forkhead transcription factor and slightly enhances proliferation. Based on a filter penetration assay, PTEN ؉/؊ cells are substantially more migratory and invasive than ؉/؉ cells. The ؉/؊ cells also are more resistant to H 2 O 2 -induced apoptosis. Analysis of PTEN ؉/؊ and ؉/؉ mice by BrdU labeling reveals no difference in the rate of cell proliferation in the SVZ. Exit of BrdU-labeled cells from the SVZ and radial migration to the outer layers of the olfactory bulb are more rapid for ؉/؊ cells. These observations indicate that PTEN regulates SVZ precursor cell function and is particularly important for migration and apoptosis in response to oxidative stress.

Journal of Experimental Medicine, 2001

A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate ... more A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate cell proliferation is via the receptor tyrosine kinase/Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The output of this pathway is subjected to tight regulation of both positive and negative regulators. One such regulator is p62 dok , the prototype of a newly identified family of adaptor proteins. We recently provided evidence, through the use of p62 dok -deficient cells, that p62 dok acts as a negative regulator of growth factor-induced cell proliferation and the Ras/MAPK pathway. We show here that reintroduction of p62 dok into p62 dok Ϫ / Ϫ cells can suppress the increased cell proliferation and prolonged MAPK activity seen in these cells, and that plasma membrane recruitment of p62 dok is essential for its function. We also show that the PDGF-triggered plasma membrane translocation of p62 dok requires activation of phosphoinositide 3-kinase (PI3-kinase) and binding of its pleckstrin homology (PH) domain to 3 Ј -phosphorylated phosphoinositides. Furthermore, we demonstrate that p62 dok can exert its negative effect on the PDGFR/MAPK pathway independently of its ability to associate with RasGAP and Nck. We conclude that p62 dok functions as a negative regulator of the PDGFR/Ras/MAPK signaling pathway through a mechanism involving PI3-kinase-dependent recruitment of p62 dok to the plasma membrane.

Nucleic Acids Research, 1991

Cancer Research, 2008

Activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling cascade is becoming increasin... more Activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling cascade is becoming increasingly recognized as a common feature of thyroid follicular neoplasms. We have recently shown that conditional loss of Pten in the mouse thyroid follicular cells is sufficient to stimulate continuous autonomous growth, leading to a homogeneously hyperplastic gland and to the development of follicular adenomas. Because the PI3K/AKT cascade can activate a plethora of different signaling pathways, it is still unclear which of these may represent the key mitogenic output of PI3K-initiated signaling.

JAMA-français, Nov 1, 2005

Endocrinology, 2013

Mouse models can provide useful information to understand molecular mechanisms of human tumorigen... more Mouse models can provide useful information to understand molecular mechanisms of human tumorigenesis. In this study, the conditional thyroid mutagenesis of Pten and Ras genes in the mouse, which induces very aggressive follicular carcinomas (FTCs), has been used to identify genes differentially expressed among human normal thyroid tissue (NT), follicular adenoma (FA), and FTC. Global gene expression of mouse FTC was compared with that of mouse normal thyroids: 911 genes were found deregulated ± 2-fold in FTC samples. Then the expression of 45 deregulated genes in mouse tumors was investigated by quantitative RT-PCR in a first cohort of human NT, FA, and FTC (discovery group). Five genes were found significantly down-regulated in FA and FTC compared with NT. However, 17 genes were found differentially expressed between FA and FTC: 5 and 12 genes were overexpressed and underexpressed in FTC vs FA, respectively. Finally, 7 gene products, selected from results obtained in the discovery group, were investigated in a second cohort of human tumors (validation group) by immunohistochemistry. Four proteins showed significant differences between FA and FTC (peroxisomal proliferator-activated receptor-γ, serum deprivation response protein, osteoglycin, and dipeptidase 1). Altogether our data indicate that the establishment of an enriched panel of molecular biomarkers using data coming from mouse thyroid tumors and validated in human specimens may help to set up a more valid platform to further improve diagnosis and prognosis of thyroid malignancies.

Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tu... more Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, includ- ing multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have

Nucleic Acids Research, 1992

ERV9 is a low repeated family of human endogenous retroviral elements whose expression is mainly ... more ERV9 is a low repeated family of human endogenous retroviral elements whose expression is mainly detectable in undifferentiated embryonal carcinoma NT2/D1 cells. In this report we have analyzed the minimal promoter region located within the ERV9 LTR. Using the transient CAT expression assay we have identified the minimal promoter region, which includes sequences spanning from -70 to + 6 relative to the major transcription start site. Deletion analysis, primer extension mapping of the transcription start sites and DNA-protein interactions assays have allowed us to define two important regions within the ERV9 minimal promoter. One region located between -70 to -39 acts as a transcriptional activating sequence and contains an Spl binding site. The second region from -7 to + 6, which resembles an initiator element (Inr), was necessary for the correct transcription start site utilization, and binds to a regulatory protein. Crosscompetition experiments using various Inr elements have indicated that the protein that binds to the ERV9 lnr element can be competed by the HIV-1 and TdT Inr sequences.

Molecular and Cellular Neuroscience, 2002

PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and me... more PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and mental deficiencies. We have used PTEN ؉/؊ mice to assess PTEN's role in subventricular zone (SVZ) precursor cells. For cultured SVZ neurosphere cells, haploinsufficiency for PTEN increases phosphorylation of Akt and forkhead transcription factor and slightly enhances proliferation. Based on a filter penetration assay, PTEN ؉/؊ cells are substantially more migratory and invasive than ؉/؉ cells. The ؉/؊ cells also are more resistant to H 2 O 2 -induced apoptosis. Analysis of PTEN ؉/؊ and ؉/؉ mice by BrdU labeling reveals no difference in the rate of cell proliferation in the SVZ. Exit of BrdU-labeled cells from the SVZ and radial migration to the outer layers of the olfactory bulb are more rapid for ؉/؊ cells. These observations indicate that PTEN regulates SVZ precursor cell function and is particularly important for migration and apoptosis in response to oxidative stress.

Journal of Experimental Medicine, 2001

A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate ... more A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate cell proliferation is via the receptor tyrosine kinase/Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The output of this pathway is subjected to tight regulation of both positive and negative regulators. One such regulator is p62 dok , the prototype of a newly identified family of adaptor proteins. We recently provided evidence, through the use of p62 dok -deficient cells, that p62 dok acts as a negative regulator of growth factor-induced cell proliferation and the Ras/MAPK pathway. We show here that reintroduction of p62 dok into p62 dok Ϫ / Ϫ cells can suppress the increased cell proliferation and prolonged MAPK activity seen in these cells, and that plasma membrane recruitment of p62 dok is essential for its function. We also show that the PDGF-triggered plasma membrane translocation of p62 dok requires activation of phosphoinositide 3-kinase (PI3-kinase) and binding of its pleckstrin homology (PH) domain to 3 Ј -phosphorylated phosphoinositides. Furthermore, we demonstrate that p62 dok can exert its negative effect on the PDGFR/MAPK pathway independently of its ability to associate with RasGAP and Nck. We conclude that p62 dok functions as a negative regulator of the PDGFR/Ras/MAPK signaling pathway through a mechanism involving PI3-kinase-dependent recruitment of p62 dok to the plasma membrane.

Nucleic Acids Research, 1991

Cancer Research, 2008

Activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling cascade is becoming increasin... more Activation of the phosphatidylinositol-3-OH kinase (PI3K) signaling cascade is becoming increasingly recognized as a common feature of thyroid follicular neoplasms. We have recently shown that conditional loss of Pten in the mouse thyroid follicular cells is sufficient to stimulate continuous autonomous growth, leading to a homogeneously hyperplastic gland and to the development of follicular adenomas. Because the PI3K/AKT cascade can activate a plethora of different signaling pathways, it is still unclear which of these may represent the key mitogenic output of PI3K-initiated signaling.

JAMA-français, Nov 1, 2005

Endocrinology, 2013

Mouse models can provide useful information to understand molecular mechanisms of human tumorigen... more Mouse models can provide useful information to understand molecular mechanisms of human tumorigenesis. In this study, the conditional thyroid mutagenesis of Pten and Ras genes in the mouse, which induces very aggressive follicular carcinomas (FTCs), has been used to identify genes differentially expressed among human normal thyroid tissue (NT), follicular adenoma (FA), and FTC. Global gene expression of mouse FTC was compared with that of mouse normal thyroids: 911 genes were found deregulated ± 2-fold in FTC samples. Then the expression of 45 deregulated genes in mouse tumors was investigated by quantitative RT-PCR in a first cohort of human NT, FA, and FTC (discovery group). Five genes were found significantly down-regulated in FA and FTC compared with NT. However, 17 genes were found differentially expressed between FA and FTC: 5 and 12 genes were overexpressed and underexpressed in FTC vs FA, respectively. Finally, 7 gene products, selected from results obtained in the discovery group, were investigated in a second cohort of human tumors (validation group) by immunohistochemistry. Four proteins showed significant differences between FA and FTC (peroxisomal proliferator-activated receptor-γ, serum deprivation response protein, osteoglycin, and dipeptidase 1). Altogether our data indicate that the establishment of an enriched panel of molecular biomarkers using data coming from mouse thyroid tumors and validated in human specimens may help to set up a more valid platform to further improve diagnosis and prognosis of thyroid malignancies.