Carboxy terminus and pore-forming domain properties specific to Cx37 are necessary for Cx37-mediated suppression of insulinoma cell proliferation.
Carboxy terminus and pore-forming domain properties specific to Cx37 are necessary for Cx37-mediated suppression of insulinoma cell proliferation.
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Cx37 特有的羧基末端和成孔结构域特性对于 Cx37 介导的胰岛素瘤细胞增殖抑制是必需的。
DOI：
10.1152/ajpcell.00159.2013
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Burt,JanisM
中科院分区：
文献类型：
--
作者：
Nelson,TashaK;Sorgen,PaulL;Burt,JanisM
连接蛋白37（Cx 37）在大鼠胰岛素瘤（Rin）细胞中表达时抑制细胞增殖，在体内血管发育期间和响应组织损伤时也表现出这种作用。具有非功能性通道但通常位于野生型羧基末端的Cx 37突变形式不具有生长抑制作用。在这里，我们确定了Cx 37介导的生长抑制是否需要羧基末端（CT）结构域，以及Cx 37孔形成结构域是否可以被Cx43孔形成结构域取代，并且仍然保留生长抑制特性。我们发现，尽管形成功能性间隙连接通道和半通道，Cx 37与残基随后273替换为V5-表位标签（Cx 37 - 273 tr *V5）对Rin细胞的增殖没有影响，没有促进G1细胞周期停滞与血清剥夺，并没有延长细胞周期时间与野生型蛋白质。嵌合体Cx43* CT 37，包括Cx43的孔形成结构域和Cx 37的CT，也不抑制增殖，尽管形成具有与野生型Cx 37类似的选择性透过特性的功能性间隙连接。Cx 37 - 273 tr *V5和Cx43* CT 37相对于其野生型对应物的通道行为的差异以及Cx 37-CT与Cx43细胞质环的相互作用的失败表明Cx 37-CT和孔形成结构域对于Cx 37的生长抑制都是必需的。
Connexin 37 (Cx37) suppresses cell proliferation when expressed in rat insulinoma (Rin) cells, an effect also manifest in vivo during vascular development and in response to tissue injury. Mutant forms of Cx37 with nonfunctional channels but normally localized, wild-type carboxy termini are not growth suppressive. Here we determined whether the carboxy-terminal (CT) domain is required for Cx37-mediated growth suppression and whether the Cx37 pore-forming domain can be replaced with the Cx43 pore-forming domain and still retain growth-suppressive properties. We show that despite forming functional gap junction channels and hemichannels, Cx37 with residues subsequent to 273 replaced with a V5-epitope tag (Cx37–273tr*V5) had no effect on the proliferation of Rin cells, did not facilitate G1-cell cycle arrest with serum deprivation, and did not prolong cell cycle time comparably to the wild-type protein. The chimera Cx43*CT37, comprising the pore-forming domain of Cx43 and CT of Cx37, also did not suppress proliferation, despite forming functional gap junctions with a permselective profile similar to wild-type Cx37. Differences in channel behavior of both Cx37–273tr*V5 and Cx43*CT37 relative to their wild-type counterparts and failure of the Cx37-CT to interact as the Cx43-CT does with the Cx43 cytoplasmic loop suggest that the Cx37-CT and pore-forming domains are both essential to growth suppression by Cx37.
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