A Potential Pathogenetic Mechanism for Multiple Endocrine Neoplasia Type 2 Syndromes Involves ret-Induced Impairment of Terminal Differentiation of Neuroepithelial Cells
Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to i...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1996-07, Vol.93 (15), p.7933-7937 |
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| creator | Califano, D. D'Alessio, A. Colucci-D'Amato, G. L. De Vita, G. Monaco, C. Santelli, G. Di Fiore, P. P. Vecchio, G. Fusco, A. Santoro, M. De Franciscis, V. |
| description | Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes. |
| doi_str_mv | 10.1073/pnas.93.15.7933 |
| format | Article |
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L. ; De Vita, G. ; Monaco, C. ; Santelli, G. ; Di Fiore, P. P. ; Vecchio, G. ; Fusco, A. ; Santoro, M. ; De Franciscis, V.</creator><creatorcontrib>Califano, D. ; D'Alessio, A. ; Colucci-D'Amato, G. L. ; De Vita, G. ; Monaco, C. ; Santelli, G. ; Di Fiore, P. P. ; Vecchio, G. ; Fusco, A. ; Santoro, M. ; De Franciscis, V.</creatorcontrib><description>Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.93.15.7933</identifier><identifier>PMID: 8755580</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Adrenal Gland Neoplasms ; Alleles ; Animals ; Cell Differentiation ; Cell growth ; Cell lines ; Chloramphenicol O-Acetyltransferase - biosynthesis ; DNA-Binding Proteins - biosynthesis ; Drosophila Proteins ; Early Growth Response Protein 1 ; Genetics ; Humans ; Immediate-Early Proteins ; Medical research ; Multiple endocrine neoplasia type 2a ; Multiple Endocrine Neoplasia Type 2a - genetics ; Multiple Endocrine Neoplasia Type 2a - pathology ; Multiple endocrine neoplasia type 2b ; Multiple Endocrine Neoplasia Type 2b - genetics ; Multiple Endocrine Neoplasia Type 2b - pathology ; Mutation ; Neurons - cytology ; Oncogenes ; PC12 Cells ; Phenotypes ; Pheochromocytoma ; Plasmids ; Proto-Oncogene Proteins - biosynthesis ; Proto-Oncogene Proteins - physiology ; Proto-Oncogene Proteins c-ret ; Proto-Oncogenes ; Rats ; Receptor Protein-Tyrosine Kinases - biosynthesis ; Receptor Protein-Tyrosine Kinases - physiology ; Recombinant Fusion Proteins - biosynthesis ; Rodents ; Transcription Factors - biosynthesis ; Transfection ; Tumors ; Zinc Fingers</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1996-07, Vol.93 (15), p.7933-7937</ispartof><rights>Copyright 1996 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Jul 23, 1996</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c520t-27e2f74d8e8647b83dc004f8d2d171cf6bf674a6927ddf3641de151999e157ba3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/93/15.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/40140$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/40140$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53769,53771,57995,58228</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8755580$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Califano, D.</creatorcontrib><creatorcontrib>D'Alessio, A.</creatorcontrib><creatorcontrib>Colucci-D'Amato, G. L.</creatorcontrib><creatorcontrib>De Vita, G.</creatorcontrib><creatorcontrib>Monaco, C.</creatorcontrib><creatorcontrib>Santelli, G.</creatorcontrib><creatorcontrib>Di Fiore, P. P.</creatorcontrib><creatorcontrib>Vecchio, G.</creatorcontrib><creatorcontrib>Fusco, A.</creatorcontrib><creatorcontrib>Santoro, M.</creatorcontrib><creatorcontrib>De Franciscis, V.</creatorcontrib><title>A Potential Pathogenetic Mechanism for Multiple Endocrine Neoplasia Type 2 Syndromes Involves ret-Induced Impairment of Terminal Differentiation of Neuroepithelial Cells</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes.</description><subject>Adrenal Gland Neoplasms</subject><subject>Alleles</subject><subject>Animals</subject><subject>Cell Differentiation</subject><subject>Cell growth</subject><subject>Cell lines</subject><subject>Chloramphenicol O-Acetyltransferase - biosynthesis</subject><subject>DNA-Binding Proteins - biosynthesis</subject><subject>Drosophila Proteins</subject><subject>Early Growth Response Protein 1</subject><subject>Genetics</subject><subject>Humans</subject><subject>Immediate-Early Proteins</subject><subject>Medical research</subject><subject>Multiple endocrine neoplasia type 2a</subject><subject>Multiple Endocrine Neoplasia Type 2a - genetics</subject><subject>Multiple Endocrine Neoplasia Type 2a - pathology</subject><subject>Multiple endocrine neoplasia type 2b</subject><subject>Multiple Endocrine Neoplasia Type 2b - genetics</subject><subject>Multiple Endocrine Neoplasia Type 2b - pathology</subject><subject>Mutation</subject><subject>Neurons - cytology</subject><subject>Oncogenes</subject><subject>PC12 Cells</subject><subject>Phenotypes</subject><subject>Pheochromocytoma</subject><subject>Plasmids</subject><subject>Proto-Oncogene Proteins - biosynthesis</subject><subject>Proto-Oncogene Proteins - physiology</subject><subject>Proto-Oncogene Proteins c-ret</subject><subject>Proto-Oncogenes</subject><subject>Rats</subject><subject>Receptor Protein-Tyrosine Kinases - biosynthesis</subject><subject>Receptor Protein-Tyrosine Kinases - physiology</subject><subject>Recombinant Fusion Proteins - biosynthesis</subject><subject>Rodents</subject><subject>Transcription Factors - biosynthesis</subject><subject>Transfection</subject><subject>Tumors</subject><subject>Zinc Fingers</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFksGO0zAQhiMEWkrhjIQEsjjAqV07TuJE4rIqC1TaXVainC03Hm9dOXawnYo-Em-JQ0vFcoDTjPR_M_OPPVn2nOA5wYye91aEeUPnpJyzhtIH2YTghsyqosEPswnGOZvVRV48zp6EsMUYN2WNz7KzmpVlyibZjwt06yLYqIVBtyJu3B1YiLpF19BuhNWhQ8p5dD2YqHsD6NJK13ptAd2A640IWqDVvgeUoy97K73rIKCl3TmzS4mHOFtaObQg0bLrhfZdmoWcQivwnbZp6HutFPhfDqJ2dtRuYPAOeh03YEZfCzAmPM0eKWECPDvGafb1w-Vq8Wl29fnjcnFxNWvLHMdZziBXrJA11FXB1jWVLcaFqmUuCSOtqtaqYoWompxJqWhVEAmkJE3TpMDWgk6zd4e-_bDuQLbJmReG9153wu-5E5rfV6ze8Du347SuyzyVvzmWe_dtgBB5p0ObFhAW3BA4q3OWBtX_BUlZ0bJMfzrNXv8Fbt3g09MFnmNCWUFznKDzA9R6F4IHdTJMMB8vhY-Xwhua-vLxUlLFyz_3PPHH00j6q6M-Fv5W7zV4-0-Aq8GYCN9jIl8cyG2Izp_QApMC0580nN80</recordid><startdate>19960723</startdate><enddate>19960723</enddate><creator>Califano, D.</creator><creator>D'Alessio, A.</creator><creator>Colucci-D'Amato, G. 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P.</creator><creator>Vecchio, G.</creator><creator>Fusco, A.</creator><creator>Santoro, M.</creator><creator>De Franciscis, V.</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19960723</creationdate><title>A Potential Pathogenetic Mechanism for Multiple Endocrine Neoplasia Type 2 Syndromes Involves ret-Induced Impairment of Terminal Differentiation of Neuroepithelial Cells</title><author>Califano, D. ; D'Alessio, A. ; Colucci-D'Amato, G. 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L.</au><au>De Vita, G.</au><au>Monaco, C.</au><au>Santelli, G.</au><au>Di Fiore, P. P.</au><au>Vecchio, G.</au><au>Fusco, A.</au><au>Santoro, M.</au><au>De Franciscis, V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Potential Pathogenetic Mechanism for Multiple Endocrine Neoplasia Type 2 Syndromes Involves ret-Induced Impairment of Terminal Differentiation of Neuroepithelial Cells</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1996-07-23</date><risdate>1996</risdate><volume>93</volume><issue>15</issue><spage>7933</spage><epage>7937</epage><pages>7933-7937</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Germ-line missense mutations of the receptor-like tyrosine kinase ret are the causative genetic event of the multiple endocrine neoplasia (MEN) type 2A and type 2B syndromes and of the familial medullary thyroid carcinoma. We have used the rat pheochromocytoma cell line, PC12, as a model system to investigate the mechanism or mechanisms by which expression of activated ret alleles contributes to the neoplastic phenotype in neuroendocrine cells. Here we show that stable expression of ret mutants (MEN2A and MEN2B alleles) in PC12 cells causes a dramatic conversion from a round to a flat morphology, accompanied by the induction of genes belonging to the early as well as the delayed response to nerve growth factor. However, in the transfected PC12 cells, the continuous expression of neuronal specific genes is not associated with the suppression of cell proliferation. Furthermore, expression of ret mutants renders PC12 cells unresponsive to nerve growth factor-induced inhibition of proliferation. These results suggest that induction of an aberrant pattern of differentiation, accompanied by unresponsiveness to growth-inhibitory physiological signals, may be part of the mechanism of action of activated ret alleles in the pathogenesis of neuroendocrine tumors associated with MEN2 syndromes.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>8755580</pmid><doi>10.1073/pnas.93.15.7933</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1996-07, Vol.93 (15), p.7933-7937 |
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| subjects | Adrenal Gland Neoplasms Alleles Animals Cell Differentiation Cell growth Cell lines Chloramphenicol O-Acetyltransferase - biosynthesis DNA-Binding Proteins - biosynthesis Drosophila Proteins Early Growth Response Protein 1 Genetics Humans Immediate-Early Proteins Medical research Multiple endocrine neoplasia type 2a Multiple Endocrine Neoplasia Type 2a - genetics Multiple Endocrine Neoplasia Type 2a - pathology Multiple endocrine neoplasia type 2b Multiple Endocrine Neoplasia Type 2b - genetics Multiple Endocrine Neoplasia Type 2b - pathology Mutation Neurons - cytology Oncogenes PC12 Cells Phenotypes Pheochromocytoma Plasmids Proto-Oncogene Proteins - biosynthesis Proto-Oncogene Proteins - physiology Proto-Oncogene Proteins c-ret Proto-Oncogenes Rats Receptor Protein-Tyrosine Kinases - biosynthesis Receptor Protein-Tyrosine Kinases - physiology Recombinant Fusion Proteins - biosynthesis Rodents Transcription Factors - biosynthesis Transfection Tumors Zinc Fingers |
| title | A Potential Pathogenetic Mechanism for Multiple Endocrine Neoplasia Type 2 Syndromes Involves ret-Induced Impairment of Terminal Differentiation of Neuroepithelial Cells |
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