Effects of the ras-related rap2 protein on cellular proliferation.

Ras oncogenes encode 21-kDa (p21s) GTP binding proteins that are capable of transforming immortalized cells in culture. The ras-related rap1A/Krev-1/smgp21A protein, that exhibits a similar structural organization and contains the same effector domain as ras proteins, antagonizes ras-transformation. In order to investigate whether the closely related (61% identical) rap2 protein had similar capacities, the corresponding cDNA was inserted into constitutive as well as inducible mammalian expression vectors. Neither the wild-type, nor an "activated" mutant carrying a glycine-to-valine substitution at position 12, had any transforming activity. Several independent lines of evidence demonstrate that the rap2 protein exhibits neither growth-promoting nor growth-inhibitory effects, and that its over-expression does not interfere with ras-induced transformation. Thus, in spite of their great similarities, the rap1A/Krev-1/smgp21A and rap2 proteins have distinct physiological properties.     

Putting the Puzzle Together

This article will describe my journey through the Master in Education program at Simon Fraser University (SFU). The focus was in Curriculum and Instruction with a twist – all my work was prepared in web-based format. Not only was I advancing my knowledge in education theory, I had to challenge my skills in computers. I will both identify the pieces of my puzzle, and consider the ways they do and don't fit together. I will share some thoughts on where my work will lead me and how it can contribute to the profession, I am very proud to be a part of.     

The role of the nuclear Akt activation and Akt inhibitors in all-trans-retinoic acid-differentiated HL-60 cells.

The pharmacological inhibitors of phosphoinositide 3-kinase (PI3K)/Akt pathway have been proposed in the treatment of leukemia based on their antiproliferative effects. However, several studies demonstrated the activation of PI3K in the nuclei of all-trans-retinoic acid (ATRA) - differentiated HL-60 cells, raising the possibility that PI3K/Akt-inhibitors may block antitumor properties of retinoids. The aim of the present study was to investigate the possible activation of nuclear Akt in ATRA-treated cells and to test the effects of Akt-inhibitors on ATRA-mediated differentiation. The Akt-activity was found to be increased in the nuclei and lysates of ATRA-differentiated HL-60 and NB4 cells. The down-modulation of the expression of Akt protein in HL-60 cells using siRNA reduces the CD11b expression in ATRA-treated cells. The treatment of both cell lines with the commercially available Akt inhibitors inhibited the growth of both control and ATRA-treated cells. Akt-inhibitors had no inhibitory effects on ATRA-mediated growth arrest and the expression of CD11b in HL-60 cells, but increased the percentage of control cells expressing CD11b. In contrast, the presence of Akt inhibitors reduced the expression of CD11b in ATRA-treated NB4 cells.     

A bad rap: Rap1 signaling and oncogenesis

In the paper by Ishida et al. in this issue of Cancer Cell, the authors report the results of targeted inactivation of a Rap1-specific GTPase-activating protein (GAP) gene, called SPA-1, in mice. Rap1 hyperactivation was observed in hematopoietic cells, which led over time to features associated with symptoms typical of human myeloid dyslastic and myeloid proliferative diseases. The authors present additional data showing that the level of Rap1 activation is important for regulating myelopoiesis and that, in the right context, can deliver an oncogenic signal.     

Putting tumors to the blood test

Detection devices that combine advances in biology, nanotechnology, and microfluidics are dramatically broadening the sensitivity and scope of "liquid biopsies" for cancer research, detection, and treatment.     

Putting tumours in context

The interactions between cancer cells and their micro- and macroenvironment create a context that promotes tumour growth and protects it from immune attack. The functional association of cancer cells with their surrounding tissues forms a new 'organ' that changes as malignancy progresses. Investigation of this process might provide new insights into the mechanisms of tumorigenesis and could also lead to new therapeutic targets.     

重视肿瘤生酮治疗的研究

肿瘤细胞Warburg效应为肿瘤生酮治疗奠定了坚实的理论基础,大量研究发现生酮疗法是肿瘤治疗的一个有效手段,生酮治疗可以直接抑制肿瘤生长、增强放化疗效果、提高生活质量、延长生存时间;既可以独立使用,也可以与肿瘤治疗其他方法联合。但是不同肿瘤对生酮治疗反应差异显著,机制不明。肿瘤生酮治疗目前以细胞株及其荷瘤动物研究较多,临床上以病例报告为主,缺乏设计严谨的对照研究。为了更好地推动肿瘤治疗的进步与发展,改善我国肿瘤治疗现状,笔者呼吁高度重视生酮疗法等代谢调节治疗,加快转化医学研究,加强临床随机对照研究,探讨生酮治疗疗效差异的原因及其机制,寻找新的、能够指导生酮饮食（ketogenic diet, KD）治疗的分子标志物,为精准筛选生酮治疗对象提供分子标志、建立预测肿瘤生酮治疗敏感度的分子诊断方法,发掘提高肿瘤生酮治疗疗效的干预靶点,从而进一步提高肿瘤治疗效果。     

Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor.

BACKGROUND: Akt has been implicated in the oncogenesis of human malignant tumors, because Akt regulates many key effector molecules involved in cell survival. PTEN (phosphatase and tensin homolog deleted on chromosome 10) negatively regulates Akt activation. MATERIALS AND METHODS: The expression of phosphorylated Akt (p-Akt), total Akt and PTEN was analyzed by Western blotting in 45 renal cell carcinoma (RCC) patients. The Bad and phosphorylated Bad (p-Bad) statuses were analyzed in 20 RCC patients. A phosphatidylinositol ether analog was used as an Akt inhibitor to treat four RCC cell lines, namely Caki-1, KU19-20, SW839 and Caki-2. RESULTS: The PTEN expression in RCC was observed to decrease and p-Akt expression to increase significantly in comparison with that in the corresponding normal kidney tissue. The PTEN expression inversely correlated with the p-Akt expression. These alterations were specific for clear cell type RCC, but not for papillary or chromophobe type RCC. Alterations in Bad phosphorylation were also specifically observed in clear cell type. The Akt inhibitor induced apoptosis in KU19-20 and Caki-2 cells with a high Akt activity. CONCLUSIONS: A decreased expression of PTEN may be an underlying mechanism for Akt activation. An Akt inhibitor may be a therapeutic option for a subset of RCC with an elevated Akt activity.     

Oncogenic transformation induced by membrane-targeted Akt2 and Akt3

The kinases Akt2, Akt3 and their myristylated variants, Myr-Akt2 and Myr-Akt3 were expressed by the RCAS vector in chicken embryo fibroblasts (CEF). Myr-Akt2 and Myr-Akt3 were strongly oncogenic, inducing multilayered foci of transformed cells. In contrast, wild-type Akt2 and Akt3 were only poorly transforming, their efficiencies of focus formation were more than 100-fold lower; foci appeared later and showed less multilayering. Addition of the myristylation signal not only enhanced oncogenic potential but also increased kinase activities. Myr-Akt2 and Myr-Akt3 also induced hemangiosarcomas in the animal, whereas wild type Akt2 and Akt3 were not oncogenic in vivo. Furthermore, Akt2, driven by the lck (lymphocyte specific kinase) promoter in transgenic mice, induced lymphomas. The oncogenic effects of Akt2 and Akt3 described here are indistinguishable from those of Akt1. The downstream targets relevant to oncogenic transformation are therefore probably shared by the three Akt kinases.