How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance.
How moderate changes in Akt T-loop phosphorylation impact on tumorigenesis and insulin resistance.
复制标题
DOI：
10.1242/dmm.005603
复制
发表时间：
2011-01
影响因子：
4.3
通讯作者：
Alessi DR
中科院分区：
文献类型：
--
作者：
Wullschleger S;Sakamoto K;Johnstone L;Duce S;Fleming S;Alessi DR
Akt信号通路在控制细胞对胰岛素的反应以及增殖和存活中起着至关重要的作用。Akt信号传导的抑制导致胰岛素抵抗和2型糖尿病，而Akt的过度活化促进肿瘤发生。在这项研究中，我们研究了Akt信号通路活性的适度变化，在某种程度上可能通过药物治疗实现，将影响胰岛素抵抗和肿瘤发生。使用胰岛素抵抗的PDK 1 K465 E/K465 E PH结构域敲入小鼠，我们发现引入PTEN+/−突变以轻微刺激Akt恢复了正常的胰岛素敏感性。将PDK 1 K465 E/K465 E PH结构域敲入突变引入易患癌症的PTEN+/−小鼠中，仅使Akt活性降低约50%，但在广泛的肿瘤中导致肿瘤发作延迟约4个月。这也伴随着缓慢增长的B细胞滤泡性淋巴瘤，通过磁共振成像监测。我们的研究结果表明，导致Akt活性适度降低的信号转导抑制剂不仅会延迟具有升高的磷酸肌醇3-激酶途径活性的肿瘤的发作，而且还会降低已发展肿瘤的生长速率。
The Akt signalling pathway plays vital roles in controlling cellular responses to insulin as well as in proliferation and survival. Inhibition of Akt signalling leads to insulin resistance and type 2 diabetes, whereas hyperactivation of Akt promotes tumorigenesis. In this study, we investigate how modest changes in the activity of the Akt signalling pathway, to an extent that might be achieved by drug treatment, would impact on insulin resistance and tumorigenesis. Using insulin-resistant PDK1K465E/K465E PH domain knock-in mice, we found that introducing the PTEN+/− mutation to slightly stimulate Akt restored normal insulin sensitivity. Introducing the PDK1K465E/K465E PH domain knock-in mutation into cancer-prone PTEN+/− mice, lowered Akt activity only by about 50%, but led to a delay in tumour onset of ∼4 months in a broad range of tumours. This was also accompanied by slower growth of B cell follicular lymphomas, as monitored by magnetic resonance imaging. Our findings imply that signal transduction inhibitors that lead to a modest reduction in Akt activity would not only delay onset of tumours possessing elevated phosphoinositide 3-kinase pathway activity but would also reduce the growth rate of developed tumours.
登录
查看更多内容
影响因子：
8.2
作者：
Wong, J. T.;Kim, P. T. W.;Peacock, J. W.;Yau, T. Y.;Mui, A. L. -F.;Chung, S. W.;Sossi, V.;Doudet, D.;Green, D.;Ruth, T. J.;Parsons, R.;Verchere, C. B.;Ong, C. J.
通讯作者：
Ong, C. J.
影响因子：
9.2
作者：
Williams, MR;Arthur, JSC;Alessi, DR
通讯作者：
Alessi, DR
影响因子：
3.9
作者：
Dummler, B.;Hemmings, B. A.
通讯作者：
Hemmings, B. A.
DOI：
10.1073/pnas.96.4.1563
发表时间：
1999-02-16
影响因子：
11.1
作者：
Podsypanina, K;Ellenson, LH;Parsons, R
通讯作者：
Parsons, R
影响因子：
10.5
作者：
Chen, Mei-Ling;Xu, Pei-Zhang;Hay, Nissim
通讯作者：
Hay, Nissim