Hypoxia-induced TIMAP upregulation in endothelial cells and TIMAP-dependent tumor angiogenesis.

IF 5 2区 生物学 Q2 CELL BIOLOGY American journal of physiology. Cell physiology Pub Date : 2024-12-01 Epub Date: 2024-09-30 DOI:10.1152/ajpcell.00054.2024
Salah Aburahess, Laiji Li, Aashiq Hussain, Marya Obeidat, Parnian Alavi, Abul K Azad, Nadia Jahroudi, Barbara J Ballermann
{"title":"Hypoxia-induced TIMAP upregulation in endothelial cells and TIMAP-dependent tumor angiogenesis.","authors":"Salah Aburahess, Laiji Li, Aashiq Hussain, Marya Obeidat, Parnian Alavi, Abul K Azad, Nadia Jahroudi, Barbara J Ballermann","doi":"10.1152/ajpcell.00054.2024","DOIUrl":null,"url":null,"abstract":"<p><p>TGFβ-inhibited membrane associated protein (TIMAP), the endothelial cell-predominant protein phosphatase 1β regulatory subunit also known as PPP1R16B, promotes in vitro endothelial cell proliferation and angiogenic sprouting. TIMAP was first identified as a target of TGF-β1-mediated repression, but the molecular pathways regulating its expression in endothelial cells are not well-defined. This study examined the role of bone morphogenetic factor 9 (BMP9), hypoxia, and angiogenic growth factors in the regulation of TIMAP expression and determined whether TIMAP plays a role in tumor angiogenesis and growth in vivo. BMP9, which potently activated the SMAD1/5/8 pathway in endothelial cells, significantly reduced TIMAP mRNA and protein expression. Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the SMAD1/5/8 pathway. Angiogenic growth factors, including VEGFA and IGF-I, raised endothelial TIMAP levels partly by attenuating SMAD1/5/8 pathway activation, but also through SMAD1/5/8-independent mechanisms. Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared with wild-type littermates. These findings indicate that TIMAP plays a critical proangiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the SMAD1/5/8 pathway and through the elaboration of angiogenic growth factors by tumor cells.<b>NEW & NOTEWORTHY</b> The protein phosphatase 1 regulatory subunit TGFβ-inhibited membrane associated protein (TIMAP), known to activate AKT in endothelial cells (EC), was shown here to be repressed by bone morphogenetic factor 9 (BMP9). Hypoxia and angiogenic growth factors induced TIMAP expression by inhibiting the BMP9 pathway. In a mouse breast cancer model, TIMAP deletion inhibited tumor angiogenesis and tumor growth. Therefore, the proangiogenic functions of TIMAP are induced by hypoxia and angiogenic growth factors.</p>","PeriodicalId":7585,"journal":{"name":"American journal of physiology. Cell physiology","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Cell physiology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1152/ajpcell.00054.2024","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/30 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

TGFβ-inhibited membrane associated protein (TIMAP), the endothelial cell-predominant protein phosphatase 1β regulatory subunit also known as PPP1R16B, promotes in vitro endothelial cell proliferation and angiogenic sprouting. TIMAP was first identified as a target of TGF-β1-mediated repression, but the molecular pathways regulating its expression in endothelial cells are not well-defined. This study examined the role of bone morphogenetic factor 9 (BMP9), hypoxia, and angiogenic growth factors in the regulation of TIMAP expression and determined whether TIMAP plays a role in tumor angiogenesis and growth in vivo. BMP9, which potently activated the SMAD1/5/8 pathway in endothelial cells, significantly reduced TIMAP mRNA and protein expression. Conversely, hypoxia and the prolyl hydroxylase inhibitor Roxadustat raised TIMAP mRNA and protein levels by inhibiting the SMAD1/5/8 pathway. Angiogenic growth factors, including VEGFA and IGF-I, raised endothelial TIMAP levels partly by attenuating SMAD1/5/8 pathway activation, but also through SMAD1/5/8-independent mechanisms. Cultured breast cancer E0771 cells released mediators that raised TIMAP expression in endothelial cells, effects that were inhibited by the VEGF inhibitor Sunitinib in conjunction with the IGF-1 inhibitor Picropodophyllin. In the mouse E0771 breast cancer model in vivo, tumor growth and tumor angiogenesis were markedly attenuated in TIMAP deficient, compared with wild-type littermates. These findings indicate that TIMAP plays a critical proangiogenic function during tumor angiogenesis in vivo, likely through hypoxia-driven inhibition of the SMAD1/5/8 pathway and through the elaboration of angiogenic growth factors by tumor cells.NEW & NOTEWORTHY The protein phosphatase 1 regulatory subunit TGFβ-inhibited membrane associated protein (TIMAP), known to activate AKT in endothelial cells (EC), was shown here to be repressed by bone morphogenetic factor 9 (BMP9). Hypoxia and angiogenic growth factors induced TIMAP expression by inhibiting the BMP9 pathway. In a mouse breast cancer model, TIMAP deletion inhibited tumor angiogenesis and tumor growth. Therefore, the proangiogenic functions of TIMAP are induced by hypoxia and angiogenic growth factors.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
内皮细胞缺氧诱导的 TIMAP 上调和 TIMAP 依赖性肿瘤血管生成。
TIMAP是内皮细胞主导蛋白磷酸酶1β调节亚基,又称PPP1R16B,可促进体外内皮细胞增殖和血管新生萌发。TIMAP 首先被确定为 TGF-β1 介导的抑制靶标,但调节其在内皮细胞中表达的分子途径尚未明确。本研究探讨了BMP9、缺氧和血管生成生长因子在TIMAP表达调控中的作用,并确定了TIMAP是否在体内肿瘤血管生成和生长中发挥作用。BMP9能有效激活内皮细胞中的SMAD1/5/8通路,显著降低TIMAP mRNA和蛋白的表达。相反,缺氧和脯氨酰羟化酶抑制剂 Roxadustat 可通过抑制 BMP9 通路提高 TIMAP mRNA 和蛋白水平。血管生成生长因子(其中最主要的是 VEGFA 和 IGF-I)部分通过抑制 BMP9 通路的激活提高内皮 TIMAP 水平,但也通过 BMP 通路的非依赖性机制提高内皮 TIMAP 水平。培养的乳腺癌 E0771 细胞释放的介质可提高内皮细胞中 TIMAP 的表达,而血管内皮生长因子抑制剂舒尼替尼和 IGF-1 抑制剂苦参碱可抑制这种效应。在小鼠 E0771 乳腺癌体内模型中,与野生型同窝鼠相比,TIMAP 缺乏者的肿瘤生长和肿瘤血管生成明显减弱。这些研究结果表明,TIMAP 在体内肿瘤血管生成过程中发挥着关键的促血管生成功能,这可能是通过缺氧驱动的 BMP9 通路抑制和肿瘤细胞生成血管生成生长因子实现的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
期刊最新文献
Animal models of haploinsufficiency revealed the isoform-specific role of GSK-3 in HFD-induced obesity and glucose intolerance. Hypoxia-induced TIMAP upregulation in endothelial cells and TIMAP-dependent tumor angiogenesis. Homeostatic regulation of brain activity: from endogenous mechanisms to homeostatic nanomachines. Innate players in Th2 and non-Th2 asthma: emerging roles for the epithelial cell, mast cell, and monocyte/macrophage network. Unlocking the mechanisms of muscle fatigue: insights from the Marion J. Siegman Award Lectures.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1