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Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure.

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Title: Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure.
Authors: Burke, Ryan M.1, Lighthouse, Janet K.1, Quijada, Pearl1, Dirkx Jr., Ronald A.1, Rosenberg, Alexander2,3, Morave, Christine S.4, Alexis, Jeffrey D.5, Small, Eric M.1,5,6,7 eric_small@urmc.rochester.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 4/10/2018, Vol. 115 Issue 15, pE3436-E3445. 10p.
Subjects: Cardiovascular diseases, Disease progression, Muscle cells, Autophagy, Cell proliferation
Abstract: Heart disease is associated with the accumulation of resident cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), leading to the development of pathological fibrosis and heart failure. However, the mechanisms underlying resident CF proliferation remain poorly defined. Here, we report that small prolinerich protein 2b (Sprr2b) is among the most up-regulated genes in CFs during heart disease. We demonstrate that SPRR2B is a regulatory subunit of the USP7/MDM2-containing ubiquitination complex. SPRR2B stimulates the accumulation of MDM2 and the degradation of p53, thus facilitating the proliferation of pathological CFs. Furthermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases in response to TGF-β1 signaling and free-radical production potentiates SPRR2B activity and cell cycle progression. Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7/MDM2 binding and p53 degradation, leading to CF cell cycle arrest. Importantly, SPRR2B expression is elevated in cardiac tissue from human heart failure patients and correlates with the proliferative state of patient-derived CFs in a process that is reversed by insulin growth factor-1 signaling. These data establish SPRR2B as a unique component of the USP7/MDM2 ubiquitination complex that drives p53 degradation, CF accumulation, and the development of pathological cardiac fibrosis. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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PubType: Academic Journal
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  Data: Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure.
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  Data: <searchLink fieldCode="AR" term="%22Burke%2C+Ryan+M%2E%22">Burke, Ryan M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Lighthouse%2C+Janet+K%2E%22">Lighthouse, Janet K.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Quijada%2C+Pearl%22">Quijada, Pearl</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Dirkx+Jr%2E%2C+Ronald+A%2E%22">Dirkx Jr., Ronald A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Rosenberg%2C+Alexander%22">Rosenberg, Alexander</searchLink><relatesTo>2,3</relatesTo><br /><searchLink fieldCode="AR" term="%22Morave%2C+Christine+S%2E%22">Morave, Christine S.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Alexis%2C+Jeffrey+D%2E%22">Alexis, Jeffrey D.</searchLink><relatesTo>5</relatesTo><br /><searchLink fieldCode="AR" term="%22Small%2C+Eric+M%2E%22">Small, Eric M.</searchLink><relatesTo>1,5,6,7</relatesTo><i> eric_small@urmc.rochester.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 4/10/2018, Vol. 115 Issue 15, pE3436-E3445. 10p.
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  Data: <searchLink fieldCode="DE" term="%22Cardiovascular+diseases%22">Cardiovascular diseases</searchLink><br /><searchLink fieldCode="DE" term="%22Disease+progression%22">Disease progression</searchLink><br /><searchLink fieldCode="DE" term="%22Muscle+cells%22">Muscle cells</searchLink><br /><searchLink fieldCode="DE" term="%22Autophagy%22">Autophagy</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+proliferation%22">Cell proliferation</searchLink>
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  Data: Heart disease is associated with the accumulation of resident cardiac fibroblasts (CFs) that secrete extracellular matrix (ECM), leading to the development of pathological fibrosis and heart failure. However, the mechanisms underlying resident CF proliferation remain poorly defined. Here, we report that small prolinerich protein 2b (Sprr2b) is among the most up-regulated genes in CFs during heart disease. We demonstrate that SPRR2B is a regulatory subunit of the USP7/MDM2-containing ubiquitination complex. SPRR2B stimulates the accumulation of MDM2 and the degradation of p53, thus facilitating the proliferation of pathological CFs. Furthermore, SPRR2B phosphorylation by nonreceptor tyrosine kinases in response to TGF-β1 signaling and free-radical production potentiates SPRR2B activity and cell cycle progression. Knockdown of the Sprr2b gene or inhibition of SPRR2B phosphorylation attenuates USP7/MDM2 binding and p53 degradation, leading to CF cell cycle arrest. Importantly, SPRR2B expression is elevated in cardiac tissue from human heart failure patients and correlates with the proliferative state of patient-derived CFs in a process that is reversed by insulin growth factor-1 signaling. These data establish SPRR2B as a unique component of the USP7/MDM2 ubiquitination complex that drives p53 degradation, CF accumulation, and the development of pathological cardiac fibrosis. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.1717423115
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        Type: general
      – SubjectFull: Disease progression
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      – SubjectFull: Muscle cells
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      – SubjectFull: Autophagy
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      – SubjectFull: Cell proliferation
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      – TitleFull: Small proline-rich protein 2B drives stress-dependent p53 degradation and fibroblast proliferation in heart failure.
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              Text: 4/10/2018
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