A Dominant Negative CREB (cAMP Response Element-Binding Protein) Isoform Inhibits Thyrocyte Growth, Thyroid-Specific Gene Expression, Differentiation, and Function
cAMP mediates the effects of TSH by regulating thyroid follicular cell proliferation, differentiation, and function. To assess the functional importance of the cAMP response element binding protein (CREB) in thyroid follicular cell regulation in vivo, we targeted the expression of a dominant negativ...
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| Veröffentlicht in: | Molecular endocrinology (Baltimore, Md.) Md.), 2000-09, Vol.14 (9), p.1448-1461 |
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| creator | Nguyen, Lynda Q Kopp, Peter Martinson, Fred Stanfield, Kristina Roth, Sanford I Jameson, J. Larry |
| description | cAMP mediates the effects of TSH by regulating
thyroid follicular cell proliferation, differentiation, and function.
To assess the functional importance of the cAMP response element
binding protein (CREB) in thyroid follicular cell regulation in
vivo, we targeted the expression of a dominant negative (DN) CREB
isoform to the thyroid glands of transgenic mice using a
tissue-specific promoter. Transgenic mice exhibited severe growth
retardation and primary hypothyroidism. Serum levels of TSH were
elevated 8-fold above normal levels, and T4 and
T3 levels were low. Histologically, the mutant
thyroid glands were characterized by poorly developed follicles that
were heterogeneous in size with diminished colloid. Ciliated thyroid
epithelial cells were observed in the transgenic thyroid glands,
suggesting a failure of follicular cell differentiation. Consistent
with this hypothesis, the DN CREB transgene inhibited the expression of
an array of genes including thyroglobulin, thyroperoxidase, and the TSH
receptor in semiquantitative RT-PCR experiments. Altered expression of
the thyroid transcription factors Pax-8, TTF-1, and TTF-2 was also
observed. These results demonstrate a critical role for CREB in thyroid
growth, differentiation, and function in vivo. |
| doi_str_mv | 10.1210/mend.14.9.0516 |
| format | Article |
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thyroid follicular cell proliferation, differentiation, and function.
To assess the functional importance of the cAMP response element
binding protein (CREB) in thyroid follicular cell regulation in
vivo, we targeted the expression of a dominant negative (DN) CREB
isoform to the thyroid glands of transgenic mice using a
tissue-specific promoter. Transgenic mice exhibited severe growth
retardation and primary hypothyroidism. Serum levels of TSH were
elevated 8-fold above normal levels, and T4 and
T3 levels were low. Histologically, the mutant
thyroid glands were characterized by poorly developed follicles that
were heterogeneous in size with diminished colloid. Ciliated thyroid
epithelial cells were observed in the transgenic thyroid glands,
suggesting a failure of follicular cell differentiation. Consistent
with this hypothesis, the DN CREB transgene inhibited the expression of
an array of genes including thyroglobulin, thyroperoxidase, and the TSH
receptor in semiquantitative RT-PCR experiments. Altered expression of
the thyroid transcription factors Pax-8, TTF-1, and TTF-2 was also
observed. These results demonstrate a critical role for CREB in thyroid
growth, differentiation, and function in vivo.</description><identifier>ISSN: 0888-8809</identifier><identifier>EISSN: 1944-9917</identifier><identifier>DOI: 10.1210/mend.14.9.0516</identifier><identifier>PMID: 10976922</identifier><language>eng</language><publisher>United States: Endocrine Society</publisher><subject>Amino Acid Sequence ; Animals ; Base Sequence ; Calcitonin - analysis ; Cattle ; Cell Differentiation ; Cell Line ; Cyclic AMP Response Element-Binding Protein - genetics ; Cyclic AMP Response Element-Binding Protein - metabolism ; Gene Expression Regulation ; Mice ; Mice, Inbred C57BL ; Mice, Inbred Strains ; Mice, Transgenic ; Promoter Regions, Genetic ; Protein Isoforms - genetics ; Protein Isoforms - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Thyroglobulin - genetics ; Thyroid Gland - cytology ; Thyroid Gland - physiology ; Thyroid Gland - ultrastructure ; Thyrotropin - blood ; Thyrotropin - genetics ; Thyroxine - blood ; Transfection ; Triiodothyronine - blood</subject><ispartof>Molecular endocrinology (Baltimore, Md.), 2000-09, Vol.14 (9), p.1448-1461</ispartof><rights>Copyright © 2000 by The Endocrine Society 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3266-768e668cd7aa0a7fc06921dbf107f2a8cad799721f8fb035e4dfbf79f35541b93</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10976922$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nguyen, Lynda Q</creatorcontrib><creatorcontrib>Kopp, Peter</creatorcontrib><creatorcontrib>Martinson, Fred</creatorcontrib><creatorcontrib>Stanfield, Kristina</creatorcontrib><creatorcontrib>Roth, Sanford I</creatorcontrib><creatorcontrib>Jameson, J. Larry</creatorcontrib><title>A Dominant Negative CREB (cAMP Response Element-Binding Protein) Isoform Inhibits Thyrocyte Growth, Thyroid-Specific Gene Expression, Differentiation, and Function</title><title>Molecular endocrinology (Baltimore, Md.)</title><addtitle>Mol Endocrinol</addtitle><description>cAMP mediates the effects of TSH by regulating
thyroid follicular cell proliferation, differentiation, and function.
To assess the functional importance of the cAMP response element
binding protein (CREB) in thyroid follicular cell regulation in
vivo, we targeted the expression of a dominant negative (DN) CREB
isoform to the thyroid glands of transgenic mice using a
tissue-specific promoter. Transgenic mice exhibited severe growth
retardation and primary hypothyroidism. Serum levels of TSH were
elevated 8-fold above normal levels, and T4 and
T3 levels were low. Histologically, the mutant
thyroid glands were characterized by poorly developed follicles that
were heterogeneous in size with diminished colloid. Ciliated thyroid
epithelial cells were observed in the transgenic thyroid glands,
suggesting a failure of follicular cell differentiation. Consistent
with this hypothesis, the DN CREB transgene inhibited the expression of
an array of genes including thyroglobulin, thyroperoxidase, and the TSH
receptor in semiquantitative RT-PCR experiments. Altered expression of
the thyroid transcription factors Pax-8, TTF-1, and TTF-2 was also
observed. These results demonstrate a critical role for CREB in thyroid
growth, differentiation, and function in vivo.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Calcitonin - analysis</subject><subject>Cattle</subject><subject>Cell Differentiation</subject><subject>Cell Line</subject><subject>Cyclic AMP Response Element-Binding Protein - genetics</subject><subject>Cyclic AMP Response Element-Binding Protein - metabolism</subject><subject>Gene Expression Regulation</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Inbred Strains</subject><subject>Mice, Transgenic</subject><subject>Promoter Regions, Genetic</subject><subject>Protein Isoforms - genetics</subject><subject>Protein Isoforms - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Thyroglobulin - genetics</subject><subject>Thyroid Gland - cytology</subject><subject>Thyroid Gland - physiology</subject><subject>Thyroid Gland - ultrastructure</subject><subject>Thyrotropin - blood</subject><subject>Thyrotropin - genetics</subject><subject>Thyroxine - blood</subject><subject>Transfection</subject><subject>Triiodothyronine - blood</subject><issn>0888-8809</issn><issn>1944-9917</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU9v1DAQxS0EokvhyhH5hKjULHb-2T5ut9tlpQJVKWfLccZdVxs72Amwn4cvikN64II4jfz0mzfjeQi9pmRJc0red-DaJS2XYkkqWj9BCyrKMhOCsqdoQTjnGedEnKAXMT4QQsuK0-fohBLBapHnC_RrhS99Z51yA_4E92qw3wGvbzcX-J1efbzBtxB77yLgzQHSrCG7sK617h7fBD-AdWd4F73xocM7t7eNHSK-2x-D18cB8Db4H8P-fFZsm33pQVtjNd6CS44_-wAxWu_O8aU1BkLyt2mDSVCuxVej09PrJXpm1CHCq8d6ir5ebe7WH7Lrz9vdenWd6SKv64zVHOqa65YpRRQzmqQv0rYxlDCTK65Vy4RgOTXcNKSooGxNY5gwRVWVtBHFKXo7-_bBfxshDrKzUcPhoBz4MUqW5wWveZ7A5Qzq4GMMYGQfbKfCUVIip1jkFIukpRRyiiU1vHl0HpsO2r_wOYcEnM2AH_v_m1Uzm2Svg3Xw547ywY_Bpfv8q-83HAmqdw</recordid><startdate>200009</startdate><enddate>200009</enddate><creator>Nguyen, Lynda Q</creator><creator>Kopp, Peter</creator><creator>Martinson, Fred</creator><creator>Stanfield, Kristina</creator><creator>Roth, Sanford I</creator><creator>Jameson, J. Larry</creator><general>Endocrine Society</general><general>Oxford University Press</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>7X8</scope></search><sort><creationdate>200009</creationdate><title>A Dominant Negative CREB (cAMP Response Element-Binding Protein) Isoform Inhibits Thyrocyte Growth, Thyroid-Specific Gene Expression, Differentiation, and Function</title><author>Nguyen, Lynda Q ; Kopp, Peter ; Martinson, Fred ; Stanfield, Kristina ; Roth, Sanford I ; Jameson, J. Larry</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3266-768e668cd7aa0a7fc06921dbf107f2a8cad799721f8fb035e4dfbf79f35541b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Amino Acid Sequence</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Calcitonin - analysis</topic><topic>Cattle</topic><topic>Cell Differentiation</topic><topic>Cell Line</topic><topic>Cyclic AMP Response Element-Binding Protein - genetics</topic><topic>Cyclic AMP Response Element-Binding Protein - metabolism</topic><topic>Gene Expression Regulation</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Inbred Strains</topic><topic>Mice, Transgenic</topic><topic>Promoter Regions, Genetic</topic><topic>Protein Isoforms - genetics</topic><topic>Protein Isoforms - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Thyroglobulin - genetics</topic><topic>Thyroid Gland - cytology</topic><topic>Thyroid Gland - physiology</topic><topic>Thyroid Gland - ultrastructure</topic><topic>Thyrotropin - blood</topic><topic>Thyrotropin - genetics</topic><topic>Thyroxine - blood</topic><topic>Transfection</topic><topic>Triiodothyronine - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nguyen, Lynda Q</creatorcontrib><creatorcontrib>Kopp, Peter</creatorcontrib><creatorcontrib>Martinson, Fred</creatorcontrib><creatorcontrib>Stanfield, Kristina</creatorcontrib><creatorcontrib>Roth, Sanford I</creatorcontrib><creatorcontrib>Jameson, J. Larry</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nguyen, Lynda Q</au><au>Kopp, Peter</au><au>Martinson, Fred</au><au>Stanfield, Kristina</au><au>Roth, Sanford I</au><au>Jameson, J. Larry</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Dominant Negative CREB (cAMP Response Element-Binding Protein) Isoform Inhibits Thyrocyte Growth, Thyroid-Specific Gene Expression, Differentiation, and Function</atitle><jtitle>Molecular endocrinology (Baltimore, Md.)</jtitle><addtitle>Mol Endocrinol</addtitle><date>2000-09</date><risdate>2000</risdate><volume>14</volume><issue>9</issue><spage>1448</spage><epage>1461</epage><pages>1448-1461</pages><issn>0888-8809</issn><eissn>1944-9917</eissn><abstract>cAMP mediates the effects of TSH by regulating
thyroid follicular cell proliferation, differentiation, and function.
To assess the functional importance of the cAMP response element
binding protein (CREB) in thyroid follicular cell regulation in
vivo, we targeted the expression of a dominant negative (DN) CREB
isoform to the thyroid glands of transgenic mice using a
tissue-specific promoter. Transgenic mice exhibited severe growth
retardation and primary hypothyroidism. Serum levels of TSH were
elevated 8-fold above normal levels, and T4 and
T3 levels were low. Histologically, the mutant
thyroid glands were characterized by poorly developed follicles that
were heterogeneous in size with diminished colloid. Ciliated thyroid
epithelial cells were observed in the transgenic thyroid glands,
suggesting a failure of follicular cell differentiation. Consistent
with this hypothesis, the DN CREB transgene inhibited the expression of
an array of genes including thyroglobulin, thyroperoxidase, and the TSH
receptor in semiquantitative RT-PCR experiments. Altered expression of
the thyroid transcription factors Pax-8, TTF-1, and TTF-2 was also
observed. These results demonstrate a critical role for CREB in thyroid
growth, differentiation, and function in vivo.</abstract><cop>United States</cop><pub>Endocrine Society</pub><pmid>10976922</pmid><doi>10.1210/mend.14.9.0516</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Amino Acid Sequence Animals Base Sequence Calcitonin - analysis Cattle Cell Differentiation Cell Line Cyclic AMP Response Element-Binding Protein - genetics Cyclic AMP Response Element-Binding Protein - metabolism Gene Expression Regulation Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Transgenic Promoter Regions, Genetic Protein Isoforms - genetics Protein Isoforms - metabolism Reverse Transcriptase Polymerase Chain Reaction Thyroglobulin - genetics Thyroid Gland - cytology Thyroid Gland - physiology Thyroid Gland - ultrastructure Thyrotropin - blood Thyrotropin - genetics Thyroxine - blood Transfection Triiodothyronine - blood |
| title | A Dominant Negative CREB (cAMP Response Element-Binding Protein) Isoform Inhibits Thyrocyte Growth, Thyroid-Specific Gene Expression, Differentiation, and Function |
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