Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levels
Tristetraprolin (TTP) is an RNA binding protein that destabilizes mRNAs of factors involved in proliferation, invasiveness, and inflammation. Disruption of the gene that codes for TTP (Zfp36) led to severe arthritis, autoimmunity, cachexia and dermatitis in mice. It has been shown that these phenoty...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2023.1265475/full |
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| author | Micaela Stedile Angela Lara Montero Martín Emilio García Solá María Victoria Goddio Inés Beckerman Emilia Bogni Marina Ayre Zaira Naguila Omar A. Coso Omar A. Coso Edith C. Kordon Edith C. Kordon |
| author_facet | Micaela Stedile Angela Lara Montero Martín Emilio García Solá María Victoria Goddio Inés Beckerman Emilia Bogni Marina Ayre Zaira Naguila Omar A. Coso Omar A. Coso Edith C. Kordon Edith C. Kordon |
| author_sort | Micaela Stedile |
| collection | DOAJ |
| description | Tristetraprolin (TTP) is an RNA binding protein that destabilizes mRNAs of factors involved in proliferation, invasiveness, and inflammation. Disruption of the gene that codes for TTP (Zfp36) led to severe arthritis, autoimmunity, cachexia and dermatitis in mice. It has been shown that these phenotypes were mostly due to excessive TNFα levels in the affected tissues. We have previously reported that TTP expression is required for lactation maintenance. Our results indicated that conditional MG TTP-KO female mice displayed early involution due to the untimely induction of pro-inflammatory pathways led mostly by TNFα overexpression. Here we show that reducing TTP levels not only affects the fully differentiated mammary gland, but also harms morphogenesis of this tissue by impairing the progenitor cell population. We found that Zfp36 expression is linked to mammary stemness in human and mice. In addition, diminishing TTP expression and activity induced apoptosis of stem-like mouse mammary cells, reduced its ability to form mammospheres in culture and to develop into complete glands when implanted into cleared mammary fat pads in vivo. Our results show that survival of the stem-like cells is compromised by increased levels of inflammatory cytokines and stimulation of signaling cascades involving NFκB, STAT3 and MAPK-p38 activation. Moreover, TNFα overexpression and the consequent p38 phosphorylation would be the leading cause of progenitor cell death upon TTP expression restriction. Taken together, our results reveal the relevance of TTP for the maintenance of the mammary progenitor cell compartment by maintaining local TNFα levels at bay. |
| first_indexed | 2024-03-08T14:49:18Z |
| format | Article |
| id | doaj.art-c53b07a7f9634f9c990f5df9c9fadcd6 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-03-08T14:49:18Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-c53b07a7f9634f9c990f5df9c9fadcd62024-01-11T04:34:59ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2024-01-011110.3389/fcell.2023.12654751265475Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levelsMicaela Stedile0Angela Lara Montero1Martín Emilio García Solá2María Victoria Goddio3Inés Beckerman4Emilia Bogni5Marina Ayre6Zaira Naguila7Omar A. Coso8Omar A. Coso9Edith C. Kordon10Edith C. Kordon11Instituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaInstituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaInstituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaInstituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaInstituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaInstituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaInstituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaFacultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Ciudad de Buenos Aires, ArgentinaInstituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaDepartamento de Fisiología, Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Ciudad de Buenos Aires, ArgentinaInstituto de Fisiología, Biología Molecular y Neurociencias, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Tecnológicas (IFIBYNE-UBA-CONICET), Ciudad de Buenos Aires, ArgentinaDepartamento de Química Biológica (DQB), Facultad de Ciencias Exactas y Naturales (FCEN), Universidad de Buenos Aires (UBA), Ciudad de Buenos Aires, ArgentinaTristetraprolin (TTP) is an RNA binding protein that destabilizes mRNAs of factors involved in proliferation, invasiveness, and inflammation. Disruption of the gene that codes for TTP (Zfp36) led to severe arthritis, autoimmunity, cachexia and dermatitis in mice. It has been shown that these phenotypes were mostly due to excessive TNFα levels in the affected tissues. We have previously reported that TTP expression is required for lactation maintenance. Our results indicated that conditional MG TTP-KO female mice displayed early involution due to the untimely induction of pro-inflammatory pathways led mostly by TNFα overexpression. Here we show that reducing TTP levels not only affects the fully differentiated mammary gland, but also harms morphogenesis of this tissue by impairing the progenitor cell population. We found that Zfp36 expression is linked to mammary stemness in human and mice. In addition, diminishing TTP expression and activity induced apoptosis of stem-like mouse mammary cells, reduced its ability to form mammospheres in culture and to develop into complete glands when implanted into cleared mammary fat pads in vivo. Our results show that survival of the stem-like cells is compromised by increased levels of inflammatory cytokines and stimulation of signaling cascades involving NFκB, STAT3 and MAPK-p38 activation. Moreover, TNFα overexpression and the consequent p38 phosphorylation would be the leading cause of progenitor cell death upon TTP expression restriction. Taken together, our results reveal the relevance of TTP for the maintenance of the mammary progenitor cell compartment by maintaining local TNFα levels at bay.https://www.frontiersin.org/articles/10.3389/fcell.2023.1265475/fullmammary glandTTPmammary stem/progenitor cellsMAPK-p38TNFα |
| spellingShingle | Micaela Stedile Angela Lara Montero Martín Emilio García Solá María Victoria Goddio Inés Beckerman Emilia Bogni Marina Ayre Zaira Naguila Omar A. Coso Omar A. Coso Edith C. Kordon Edith C. Kordon Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levels Frontiers in Cell and Developmental Biology mammary gland TTP mammary stem/progenitor cells MAPK-p38 TNFα |
| title | Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levels |
| title_full | Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levels |
| title_fullStr | Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levels |
| title_full_unstemmed | Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levels |
| title_short | Tristetraprolin promotes survival of mammary progenitor cells by restraining TNFα levels |
| title_sort | tristetraprolin promotes survival of mammary progenitor cells by restraining tnfα levels |
| topic | mammary gland TTP mammary stem/progenitor cells MAPK-p38 TNFα |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2023.1265475/full |
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