KIF2C:a novel link between Wnt/β-catenin and mTORCI signaling in the pathogenesis of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common primary liver malignancy and is the fourth-leading cause of cancer-related deaths worldwide.HCC is refractory to many standard cancer treatments and the prognosis is often poor,highlighting a pressing need to identify biomarkers of aggressiveness and potential targets for future treatments.Kinesin family member 2C(KIF2C)is reported to be highly expressed in several human tumors.Nevertheless,the molecular mechanisms underlying the role of KIF2C in tumor development and progression have not been investigated.In this study,we found that KIF2C expression was significantly upregulated in HCC,and that KIF2C up-regulation was associated with a poor prognosis.Utilizing both gain and loss of function assays,we showed that KIF2C promoted HCC cell proliferation,migration,invasion,and metastasis both in vitro and in vivo.Mechanistically,we identified TBC1D7 as a binding partner of KIF2C,and this interaction disrupts the formation of the TSC complex,resulting in the enhancement of mammalian target of rapamycin complexl(mTORCI)signal transduction.Additionally,we found that KIF2C is a direct target of the Wnt/β-catenin pathway,and acts as a key factor in mediating the crosstalk between Wnt/β-catenin and mTORCI signaling.Thus,the results of our study establish a link between Wnt/β-catenin and mTORCI signaling,which highlights the potential of KIF2C as a therapeutic target for the treatment of HCC.

ATP6V0d2 mediates leucine-induced mTORCI activation and polarization of macrophages

Dear Editor, mTORCI, as a center regulatory hub of metabolism, senses the cellular energy status, nutrition and extracellular stimuli and regulates cell growth, differentiation and functions of immune cells (Powell et al., 2012). Lysosomal localization of key signal comp orients is critical for mTORCI activati on: mTORCI activation requires co-localization of activated Rheb and mTORCI to the lysosome membrane (Buerger et al., 2006). Signals in eluding growth factors, cellular stresses and energy levels act on the disruption the formation of tuberous sclerosis complex (TSC) complex, comprised of TSC1, TSC2 and TBC1D7, which leads to the translocation and activation of Rheb on the lysosome membrane (Dibble et al., 2012). In response to nutrient levels, specifically the availability of amino acids and glucose (Efeyan et al., 2013), mTORCI is recruited to the lysosomal surface by Rag GTPases that are heterodimers of RagA or RagC bound to RagB or RagD. Multiple protein complexes have been implicated in regulation of mTORCI upon nutrient sensing including Ragulator, GATOR1, GATOR2, KICSTOR and vacuolar ATPases (Wolfson et al., 2017). Vacuolar ATPases are large multiple-protein complexes that acidify the lysosome and may mediate additional functions independent of their proton pump activity (Nishi and Forgac, 2002).

氨基酸缺乏诱导细胞自噬及miRNA调控机制

氨基酸是生物体内不可缺少的营养成分和生命活动最基本的物质之一,并对动物体的新陈代谢起到至关重要的作用。自噬是细胞内通过降解和回收细胞内生物大分子和受损细胞器,以完成本身代谢和某些细胞器更新的过程。研究证实氨基酸缺乏能诱导细胞自噬,而这种反应大部分是依赖于m TORC1信号通路的方式实现的,但总氨基酸或单体氨基酸调节细胞自噬的分子作用机制和自噬水平有很大差别,且相关方面的分子调节机制尚未完全清楚,需要进一步阐明。mi RNA是一类长度为18-24 nt的非编码核苷酸,参与细胞增殖、分化、自噬与凋亡等多种生命活动。研究表明mi RNA在氨基酸缺乏诱导细胞自噬过程中的也发挥重要调控机制。就不同氨基酸缺乏调控自噬相关机制加以综述,并探讨mi RNA在其中起到的关键作用。旨在为治疗自噬相关代谢提供思路。

葡萄糖通过mTORC1信号通路调控成纤维细胞增殖

目的研究葡萄糖对小鼠皮肤成纤维细胞增殖的影响。方法将小鼠皮肤成纤维细胞培养在含不同浓度葡萄糖的培养基里,用MTT法检测细胞增殖,7-MGTP pulldown实验检测细胞翻译起始情况,Western blot检测mTORC1信号通路分子的活化。结果与培养基葡萄糖浓度为5.5 mmol/L相比较,当浓度为15 mmol/L时,促进细胞增殖,与7-MGTP结合的翻译起始复合物增加,mTORC1信号通路活化;当25 mmol/L时,抑制细胞增殖,与7-MGTP结合的翻译始复合物减少,mTORC1信号通路中与细胞增殖相关的4EBP1和与细胞生存相关的Akt的磷酸化减弱。结论葡萄糖通过对mTORC1信号通路的双向调节作用调控成纤维细胞增殖。

Effects of naringin, a flavanone glycoside in grapefruits and citrus fruits, on the nigrostriatal dopaminergic projection in the adult brain

Recently, we have demonstrated the ability of naringin, a well-known flavanone glycoside of grapefruits and citrus fruits, to prevent neurodegeneration in a neurotoxin model of Parkinson＇s disease. Intraperitoneal injection of naringin protected the nigrostriatal dopaminergic projection by increasing glial cell line-derived neurotrophic factor expression and decreasing the level of tumor necrosis factor-alpha in dopaminergic neurons and microglia, respectively. These results suggest that naringin can impart to the adult dopaminergic neurons the ability to produce glial cell line-derived neurotrophic factor against Parkinson＇s disease with anti-inflammatory effects. Based on these results, we would like to describe an important perspective on its possibility as a therapeutic agent for Parkinson＇s disease.

DAPK1(death associated protein kinase 1)mediates mTORC1 activation and antiviral activities in CD8^(+)T cells

Mechanistic target of rapamycin complex 1(mTORCt)regulates CD8^(+)T-cell differentiation and function.Despite the links between PI3K-AKT and mTORCI activation in CD8^(+)T cells,the molecular mechanism underlying mTORCI activation remains undear.Here,we show that both the kinase activity and the death domain of DAPK1 are required for maximal mTOR activation and CD8^(+)T-cell function.We found that TCR-induced activation of calcineurin activates DAPK1,which subsequently interacts with TSC2 via its death domain and phosphorylates TSC2 to mediate mTORCI activation.Furthermore,both the kinase domain and death domain of DAPK1 are required for CD8^(+)T-cell antiviral responses in an LCMV infection model.Together,our data reveal a novel mechanism of mTORCI activation that mediates optimal CD8^(+)T-cell function and antiviral activity.