Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase
Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase
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DOI：
10.1073/pnas.0504378102
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发表时间：
2005-07-19
影响因子：
11.1
通讯作者：
Cantley, LC
中科院分区：
文献类型：
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作者：
Luo, J;Sobkiw, CL;Cantley, LC
PTEN肿瘤抑制基因的杂合缺失的小鼠会发展出一系列上皮肿瘤和淋巴样增生。先前的研究表明，PTEN通过充当磷酸肌醇磷酸酶来抑制肿瘤形成，以限制磷酸肌醇3-激酶（PI3K）的信号传导。在这里，我们研究了删除PI3K（p85 alpha和p85β）对PTEN +/-小鼠中上皮肿瘤和淋巴增生的各种调节亚基的影响。有趣的是，我们发现一个p85a等位基因的损失有或没有p85β的损失导致肠道息肉的发生率增加。 PTEN（+/-）p85 alpha（+/-）p85β（ - / - ）息肉在PTEN（+/-）p85 alpha（+/-）PI3K下游的信号传导增强，这是由两个细胞增加了带有转录因子whir和细胞的细胞质染色的细胞分数增加的，该细胞与细胞的细胞质染色和细胞一起使用。增殖标记KI-67的阳性染色。相比之下，PTEN +/-小鼠p85 alpha或p85β的NULL杂合子的前列腺上皮内肿瘤的发生率并未显着改变，而在小鼠缺少P85 Beta的小鼠中，前列腺内部性肿瘤中的前列腺内上皮细胞中增殖细胞的一部分会减少。最后，尽管在p85 alpha（+/-）背景中，抗CD3刺激的Akt激活有所降低，但具有各种p85缺失的PTEN +/-小鼠的T淋巴细胞增生没有显着变化。这些结果表明，降低不同p85调节亚基的水平会导致某些组织中的PI3K信号增强，而其他组织的PI3K信号降低，但支持该模型，尽管p85蛋白对于I-A类PI3K的信号至关重要，但它们可以充当抑制剂的抑制剂。 PI3K在某些组织中的信号传导，从而抑制肿瘤的形成。
Mice with heterozygous deletion of the PTEN tumor suppressor gene develop a range of epithelial neoplasia as well as lymphoid hyperplasia. Previous studies suggest that PTEN suppresses tumor formation by acting as a phosphoinositide phosphatase to limit signaling by phosphoinositide 3-kinase (PI3K). Here, we examined the effect of deleting various regulatory subunits of PI3K(p85 alpha and p85 beta) on epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice. Interestingly, we found the loss of one p85a allele with or without the loss of p85 beta led to increased incidence of intestinal polyps. Signaling downstream of PI3K was enhanced in the PTEN(+/-)p85 alpha(+/-)p85 beta(-/-) polyps, as judged by an increased fraction of both cells with cytoplasmic staining of the transcription factor WHIR and cells with positive staining for the proliferation marker Ki-67. In contrast, the incidence of prostate intraepithelial neoplasia was not significantly altered in PTEN+/- mice heterozygous for p85 alpha or null for p85 beta, whereas the fraction of proliferating cells in prostate intraepithelial neoplasia was reduced in mice lacking p85 beta. Finally, there was no significant change in T lymphocyte hyperplasia in the PTEN+/- mice with various p85 deletions, although anti-CD3-stimulated AKT activation was somewhat reduced in the p85 alpha(+/-) background. These results indicate that decreasing the levels of different p85 regulatory subunits can result in enhanced PI3K signaling in some tissues and decreased PI3K signaling in others, supporting the model that, although p85 proteins are essential for class I-A PI3K signaling, they can function as inhibitors of PI3K signaling in some tissues and thus suppress tumor formation.