Intracellular calcium links milk stasis to lysosome-dependent cell death during early mammary gland involution.
Intracellular calcium links milk stasis to lysosome-dependent cell death during early mammary gland involution.
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DOI：
10.1007/s00018-023-05044-8
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发表时间：
2024-01-12
影响因子：
8
通讯作者：
Wysolmerski, John
中科院分区：
文献类型：
--
作者：
Jeong, Jaekwang;Lee, Jongwon;Talaia, Gabriel;Kim, Wonnam;Song, Junho;Hong, Juhyeon;Yoo, Kwangmin;Gonzalez, David G.;Athonvarangkul, Diana;Shin, Jaehun;Dann, Pamela;Haberman, Ann M.;Kim, Lark Kyun;Ferguson, Shawn M.;Choi, Jungmin;Wysolmerski, John
哺乳后乳腺的退化是细胞协调死亡的一个戏剧性的例子。断奶导致肺泡结构由于乳汁的积累而膨胀，这反过来激活STAT 3并启动半胱天冬酶非依赖性但溶酶体依赖性细胞死亡（LDCD）途径。虽然STAT 3和LDCD在早期乳房退化中的重要性已经得到了很好的证实，但乳汁淤积如何激活STAT 3还不完全清楚。在这份报告中，我们证明了PMCA 2钙泵的蛋白质水平在实验性乳汁淤积的2-4小时内显著下调。PMCA 2表达的减少与体内细胞质钙的增加相关，如通过GCaMP 6 f荧光的多光子活体成像所测量的。这些事件与核pSTAT 3表达的出现同时发生，但在LDCD或其先前涉及的介质如LIF、IL 6和TGFβ3的显著活化之前发生，所有这些介质似乎都被增加的细胞内钙上调。我们进一步证明，增加细胞内钙激活STAT 3通过诱导其负调节，SOCS 3降解。我们还观察到乳汁淤滞、PMCA 2表达丧失和细胞内钙水平升高激活TFEB，TFEB是通过涉及抑制CDK 4/6和细胞周期进程的过程来调节溶酶体生物发生的重要调节剂。总之，这些数据表明，细胞内钙作为一个重要的近端生化信号，连接乳汁淤滞STAT 3激活，增加溶酶体生物合成，和溶酶体介导的细胞死亡。在线版本包含补充材料，可通过10.1007/s 00018 -023-05044-8获取。
Involution of the mammary gland after lactation is a dramatic example of coordinated cell death. Weaning causes distension of the alveolar structures due to the accumulation of milk, which, in turn, activates STAT3 and initiates a caspase-independent but lysosome-dependent cell death (LDCD) pathway. Although the importance of STAT3 and LDCD in early mammary involution is well established, it has not been entirely clear how milk stasis activates STAT3. In this report, we demonstrate that protein levels of the PMCA2 calcium pump are significantly downregulated within 2–4 h of experimental milk stasis. Reductions in PMCA2 expression correlate with an increase in cytoplasmic calcium in vivo as measured by multiphoton intravital imaging of GCaMP6f fluorescence. These events occur concomitant with the appearance of nuclear pSTAT3 expression but prior to significant activation of LDCD or its previously implicated mediators such as LIF, IL6, and TGFβ3, all of which appear to be upregulated by increased intracellular calcium. We further demonstrate that increased intracellular calcium activates STAT3 by inducing degradation of its negative regulator, SOCS3. We also observed that milk stasis, loss of PMCA2 expression and increased intracellular calcium levels activate TFEB, an important regulator of lysosome biogenesis through a process involving inhibition of CDK4/6 and cell cycle progression. In summary, these data suggest that intracellular calcium serves as an important proximal biochemical signal linking milk stasis to STAT3 activation, increased lysosomal biogenesis, and lysosome-mediated cell death. The online version contains supplementary material available at 10.1007/s00018-023-05044-8.
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影响因子：
7.7
作者：
Jeong, Eutteum;Brady, Owen A.;Puertollano, Rosa
通讯作者：
Puertollano, Rosa
DOI：
10.1073/pnas.94.7.3425
发表时间：
1997-04-01
影响因子：
11.1
作者：
Li, ML;Liu, XW;Furth, PA
通讯作者：
Furth, PA
影响因子：
4.4
作者：
Gu Z;Eils R;Schlesner M;Ishaque N
通讯作者：
Ishaque N
影响因子：
16.6
作者：
Napolitano G;Esposito A;Choi H;Matarese M;Benedetti V;Di Malta C;Monfregola J;Medina DL;Lippincott-Schwartz J;Ballabio A
通讯作者：
Ballabio A
DOI：
10.1186/bcr43
发表时间：
2000
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Donovan J;Slingerland J
通讯作者：
Slingerland J