Essential role of the p110beta subunit of phosphoinositide 3-OH kinase in male fertility.
Essential role of the p110beta subunit of phosphoinositide 3-OH kinase in male fertility.
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DOI：
10.1091/mbc.e09-08-0744
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发表时间：
2010-03-01
影响因子：
3.3
通讯作者：
Hirsch E
中科院分区：
文献类型：
--
作者：
Ciraolo E;Morello F;Hobbs RM;Wolf F;Marone R;Iezzi M;Lu X;Mengozzi G;Altruda F;Sorba G;Guan K;Pandolfi PP;Wymann MP;Hirsch E
在缺乏p110β功能的情况下，由于分化的精原细胞的进行性减少，精子发生受到显著干扰。转基因小鼠和p110β的药理学抑制证实该酶是c-Kit下游活化的主要PI 3 K亚型。磷脂酰肌醇3-激酶（PI 3 K）是男性生育力的关键分子。然而，不同的p110 PI 3 K催化亚基在生精细胞系中的具体作用至今尚未被确定。在此，我们报告了表达无催化活性的p110β的雄性小鼠发生睾丸萎缩和精子发生受损，导致少精子症和生育力缺陷的表型。对来自p110β缺陷小管的睾丸的检查表明，由于减数分裂前和后细胞的增殖和存活缺陷，生精细胞广泛丢失。特别是，p110β在c-Kit介导的精原细胞扩增中至关重要，因为c-Kit阳性细胞在成年睾丸中丢失，SCF对Akt的激活被p110β抑制剂阻断。这些数据表明，在精子发生过程中需要c-Kit激活p110β PI 3 K亚型，从而为c-Kit阳性睾丸癌的新治疗开辟了道路。
In the absence of p110β function, spermatogenesis is dramatically disturbed because of a progressive reduction of differentiating spermatogones. Genetically modified mice and pharmacological inhibition of p110β confirmed this enzyme as the main PI3K isoform activated downstream of c-Kit. Phosphoinositide 3-kinases (PI3K) are key molecular players in male fertility. However, the specific roles of different p110 PI3K catalytic subunits within the spermatogenic lineage have not been characterized so far. Herein, we report that male mice expressing a catalytically inactive p110β develop testicular hypotrophy and impaired spermatogenesis, leading to a phenotype of oligo-azoospermia and defective fertility. The examination of testes from p110β-defective tubules demonstrates a widespread loss in spermatogenic cells, due to defective proliferation and survival of pre- and postmeiotic cells. In particular, p110β is crucially needed in c-Kit–mediated spermatogonial expansion, as c-Kit–positive cells are lost in the adult testis and activation of Akt by SCF is blocked by a p110β inhibitor. These data establish that activation of the p110β PI3K isoform by c-Kit is required during spermatogenesis, thus opening the way to new treatments for c-Kit positive testicular cancers.
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影响因子：
30.5
作者：
通讯作者：
--
影响因子：
20.3
作者：
Canobbio, Ilaria;Stefanini, Lucia;Torti, Mauro
通讯作者：
Torti, Mauro
影响因子：
64.8
作者：
Ali, K;Bilancio, A;Vanhaesebroeck, B
通讯作者：
Vanhaesebroeck, B
影响因子：
3.6
作者：
Rothschild, G;Sottas, CM;Besmer, P
通讯作者：
Besmer, P
影响因子：
7.3
作者：
Ciraolo E;Iezzi M;Marone R;Marengo S;Curcio C;Costa C;Azzolino O;Gonella C;Rubinetto C;Wu H;Dastrù W;Martin EL;Silengo L;Altruda F;Turco E;Lanzetti L;Musiani P;Rückle T;Rommel C;Backer JM;Forni G;Wymann MP;Hirsch E
通讯作者：
Hirsch E