Protein kinase C δ enhances proliferation and survival of murine mammary cells
Protein kinase C δ enhances proliferation and survival of murine mammary cells
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DOI：
10.1002/mc.20287
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发表时间：
2007-05-01
影响因子：
4.6
通讯作者：
Urtreger, Alejandro J.
中科院分区：
文献类型：
--
作者：
Grossoni, Valeria C.;Falbo, Karina B.;Urtreger, Alejandro J.
蛋白激酶C (PKC) delta是PKC丝氨酸-苏氨酸激酶新家族的一员，在包括乳腺癌细胞系在内的许多细胞类型中与增殖和凋亡的负调控有关，并被认为是一种肿瘤抑制基因。在这项研究中，我们发现在小鼠NMuMG乳腺细胞中PKC三角洲促进有丝分裂反应。NMuMG细胞中PKC δ的过表达导致[H-3]-tymidine掺入和细胞增殖显著增加，以及细胞外信号调节激酶(ERK)-丝裂原活化蛋白激酶（MAPK）活化增强。磷酸化酯激活PKC δ导致cyclin D1表达升高和Rb状态过度磷酸化。令人惊讶的是，PKC δ的异位表达赋予了NMuMG细胞不依赖锚定的生长能力。PKC δ过表达者表现出对凋亡刺激（如血清剥夺或阿霉素治疗）的增强抗性，这一效应与Akt存活通路的过度激活有关。我们的研究结果为PKC δ作为永生化乳腺细胞增殖和存活信号的积极调节剂的作用提供了证据。PKC δ根据细胞环境产生不同的反应，这一事实不仅强调了仔细理解每种细胞类型中由PKC控制的信号事件的必要性，而且表明我们应该谨慎考虑将这种激酶作为癌症治疗的靶点。(c) 2007 Wiley-Liss, Inc。
Protein kinase C (PKC) delta, a member of the novel family of PKC serine-threonine kinases, has been implicated in negative regulation of proliferation and apoptosis in a large number of cell types, including breast cancer cell lines, and postulated as a tumor suppressor gene. In this study we show that in murine NMuMG mammary cells PKC delta promotes a mitogenic response. Overexpression of PKC delta in NMuMG cells leads to a significant increase in [H-3]-tymidine incorporation and cell proliferation, as well as enhanced extracellular signal-regulated kinase (ERK)-mitogen-activated protein kinase (MAPK) activation. Activation of PKC delta with a phorbol ester leads to elevated cyclin D1 expression and an hyperphosphorylated Rb state. Surprisingly, ectopic expression of PKC delta conferred anchorage-independent growth capacity to NMuMG cells. PKC delta overexpressors showed enhanced resistance to apoptotic stimuli, such as serum deprivation or doxorubicin treatment, an effect that correlates with hyperactivation of the Akt survival pathway. Our results provide evidence for a role of PKC delta as a positive modulator of proliferative and survival signals in immortalized mammary cells. The fact that PKC delta exerts differential responses depending on the cell context not only highlights the necessity to carefully understand the signaling events controlled by this PKC in each cell type but also suggests that we should be cautious in considering this kinase a target for cancer therapy. (c) 2007 Wiley-Liss, Inc.