Activin A is a prominent autocrine regulator of hepatocyte growth arrest.
Activin A is a prominent autocrine regulator of hepatocyte growth arrest.
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DOI：
10.1002/hep4.1106
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发表时间：
2017-11
影响因子：
5.1
通讯作者：
Oertel M
中科院分区：
文献类型：
--
作者：
Haridoss S;Yovchev MI;Schweizer H;Megherhi S;Beecher M;Locker J;Oertel M
激活素A是一种多功能细胞因子，在肝细胞生长抑制中起重要作用，并参与肝脏大小的控制。本研究旨在确定激活素A在正常大鼠肝脏微环境中的细胞位置，以及激活素A信号对肝细胞表型的贡献，从而深入了解其分子机制。免疫组织化学和原位杂交分析发现，肝细胞是正常肝脏中激活素A阳性的主要细胞群，肥大细胞是激活素A的另一个来源。为了研究副分泌和自分泌激活素A刺激的作用，我们将肝细胞与工程激活素A分泌细胞系（RF1, TL8）共培养，或用编码激活素βA的腺相关病毒载体转导，导致细胞周期相关基因（Ki - 67， E2F转录因子1 [E2F1]，小染色体维持复合物组分2 [Mcm2]）的表达显著改变。叉头盒M1 [FoxM1])和衰老相关基因（细胞周期蛋白依赖性激酶抑制剂2B [p15INK4b/CDKN2B]，分化胚胎软骨细胞表达基因1 [DEC1]），减少增殖和诱导衰老。微阵列分析鉴定了453个差异表达基因，其中许多尚未被识别为激活素A的下游靶点（例如ADAM金属肽酶结构域12 [Adam12]，信号蛋白7A [Sema7a]， LIM和半胱氨酸丰富结构域1 [Lmcd1]， DAB2，网格蛋白衔接蛋白[DAB2]）。激活素A介导的主要分子/细胞功能包括细胞生长/增殖和运动、分子运输和含有高度下调基因的代谢过程，如细胞色素P450亚家族2、多肽11 （Cyp2C11）、硫转移酶家族1A成员1 （Sult1a1）、甘氨酸- N -酰基转移酶（Glyat）和胆汁酸-辅酶A：氨基酸N -酰基转移酶（Baat）。此外，匠心途径分析发现，由肝细胞核因子（HNF）‐4α和过氧化物酶体增殖物激活受体γ (PPARγ)调节的特定基因网络是激活素A信号传导的关键靶点。结论：我们的体外模型表明，激活素A刺激的生长抑制和细胞衰老是通过p15INK4b/CDKN2B介导的，并且与肝细胞进行的多种生物学过程中涉及的许多靶基因的上调和下调有关，这表明激活素A在正常肝功能中起着关键作用。（肝病通讯2017；1:852‐870）
Activin A, a multifunctional cytokine, plays an important role in hepatocyte growth suppression and is involved in liver size control. The present study was aimed to determine the cell location of activin A in the normal rat liver microenvironment and the contribution of activin A signaling to the hepatocyte phenotype to obtain insight into molecular mechanisms. Immunohistochemical and in situ hybridization analyses identified hepatocytes as the major activin A‐positive cell population in normal liver and identified mast cells as an additional activin A source. To investigate paracrine and autocrine activin A‐stimulated effects, hepatocytes were cocultured with engineered activin A‐secreting cell lines (RF1, TL8) or transduced with an adeno‐associated virus vector encoding activin βA, which led to strikingly altered expression of cell cycle‐related genes (Ki‐67, E2F transcription factor 1 [E2F1], minichromosome maintenance complex component 2 [Mcm2], forkhead box M1 [FoxM1]) and senescence‐related genes (cyclin‐dependent kinase inhibitor 2B [p15INK4b/CDKN2B], differentiated embryo‐chondrocyte expressed gene 1 [DEC1]) and reduced proliferation and induction of senescence. Microarray analyses identified 453 differentially expressed genes, many of which were not yet recognized as activin A downstream targets (e.g., ADAM metallopeptidase domain 12 [Adam12], semaphorin 7A [Sema7a], LIM and cysteine‐rich domains‐1 [Lmcd1], DAB2, clathrin adaptor protein [Dab2]). Among the main activin A‐mediated molecular/cellular functions are cellular growth/proliferation and movement, molecular transport, and metabolic processes containing highly down‐regulated genes, such as cytochrome P450, subfamily 2, polypeptide 11 (Cyp2C11), sulfotransferase family 1A, member 1 (Sult1a1), glycine‐N‐acyltransferase (Glyat), and bile acid‐CoA:amino acid N‐acyltransferase (Baat). Moreover, Ingenuity Pathway Analyses identified particular gene networks regulated by hepatocyte nuclear factor (HNF)‐4α and peroxisome proliferator‐activated receptor gamma (PPARγ) as key targets of activin A signaling. Conclusion: Our in vitro models demonstrated that activin A‐stimulated growth inhibition and cellular senescence is mediated through p15INK4b/CDKN2B and is associated with up‐ and down‐regulation of numerous target genes involved in multiple biological processes performed by hepatocytes, suggesting that activin A fulfills a critical role in normal liver function. (Hepatology Communications 2017;1:852‐870)
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DOI：
10.1083/jcb.200612046
发表时间：
2007-07-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Atfi A;Dumont E;Colland F;Bonnier D;L'helgoualc'h A;Prunier C;Ferrand N;Clément B;Wewer UM;Théret N
通讯作者：
Théret N
影响因子：
2.1
作者：
Ashida, Yuhei;Nakajima-Koyama, May;Nishida, Eisuke
通讯作者：
Nishida, Eisuke
影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
DOI：
10.1097/00042737-200302000-00004
发表时间：
2003-02-01
影响因子：
2.1
作者：
Hughes, RD;Evans, LW
通讯作者：
Evans, LW
影响因子：
3
作者：
Bale, Shyam Sundhar;Golberg, Inna;Yarmush, Martin L.
通讯作者：
Yarmush, Martin L.