Pim-2基因与造血系统肿瘤

Pim-2原癌基因属于丝氨酸苏氨酸激酶家族,具有抗凋亡以及在生长因子与细胞因子刺激下维持造血细胞生存、调节造血细胞生长及分化的特性。Pim-2过表达可以协同c—myc基因促进鼠及人类淋巴瘤的形成,深入研究Pim-2基因及其抑制剂可望为造血系统恶性肿瘤的治疗开辟新途径。     

癌基因Pim-1在肿瘤中的研究

癌基因Pim-1与多种肿瘤的发生发展密切相关,参与多个信号转导通路,调节下游生物因子的表达,或与其他癌基因协同作用,在相关肿瘤的诊断、治疗及预后评估中具有重要作用,同时也提供了新的潜在靶点.目前以Pim-1为靶点,探索治疗肿瘤的新策略成为研究热点,将有望用于肿瘤临床治疗.     

Pim-1在肿瘤及相关信号通路中的作用

原癌基因蛋白质c-pim-1(Pim-1)在肿瘤组织中常表达增高且与肿瘤分期、预后密切相关.研究表明,Pim-1不仅参与调控细胞增殖和凋亡,在肿瘤转移过程中也发挥重要作用.多个信号传导通路可以调控Pim-1表达与活化,同时Pim-1也可影响通路中多个重要因子,其在肿瘤发生发展中作用十分广泛,已成为肿瘤治疗的潜在靶点.     

p57^kip2与肿瘤

p57^kip2基因的编码产物是一种广泛的细胞周期蛋白依赖性激酶(CDK)的抑制蛋白。它通过调控细胞周期进程，参与肿瘤细胞的增殖、分化与凋亡。在多种肿瘤中均发现p57^kip2基因表达异常，且在某些肿瘤中是一种独立的预后因素，与肿瘤的发生、发展及预后有着密切关系。     

PLK1小分子抑制剂的肿瘤治疗新策略

Polo样激酶1（polo-like kinase 1,PLK1）是一类广泛存在的丝氨酸／苏氨酸蛋白激酶,其结构和功能高度保守。PLK1在肿瘤的发生及发展中起重要作用,使其成为肿瘤治疗的重要靶点。目前,已发现的PLK1小分子抑制剂有几十种,通过不同分子机制抑制PLK1功能,进而产生肿瘤抑制作用。本文针对PLK1小分子抑制剂在肿瘤治疗中的研究进展作一综述。     

丝/苏氨酸激酶Pim-3与消化道肿瘤的研究进展

Pim-3作为Pim激酶家族的新成员,通过磷酸化众多特异性底物,可能在细胞周期和细胞凋亡进程中起重要调控作用;同时,其在成体组织中的表达上调可导致某些恶性肿瘤的发生,现就目前国内外关于Pim-3激酶与消化道肿瘤的研究进展做一综述.     

丝/苏氨酸激酶Pim-3与消化道肿瘤的研究进展

Pim-3作为Pim激酶家族的新成员,通过磷酸化众多特异性底物,可能在细胞周期和细胞凋亡进程中起重要调控作用;同时,其在成体组织中的表达上调可导致某些恶性肿瘤的发生,现就目前国内外关于Pim-3激酶与消化道肿瘤的研究进展做一综述。     

p57kip2与肿瘤

p57kip2基因的编码产物是一种广泛的细胞周期蛋白依赖性激酶(CDK)的抑制蛋白.它通过调控细胞周期进程,参与肿瘤细胞的增殖、分化与凋亡.在多种肿瘤中均发现p57kip2基因表达异常,且在某些肿瘤中是一种独立的预后因素,与肿瘤的发生、发展及预后有着密切关系.     

卵巢上皮源性肿瘤Polo样激酶1的表达及其与p34cdc2的相关性

目的:探讨Polo样激酶1(plk1)、p34cdc2在卵巢上皮源性肿瘤组织中的表达及与卵巢癌各临床病理特征的关系.方法:免疫组化SP法对正常卵巢及卵巢上皮良性肿瘤、卵巢癌组织中的plk4、p34cdc2进行检测.结果:卵巢癌组织中的plk1、p34cdc2阳性表达率分别为80.8%(38/47)和63.8%(30/47).plk1与p34cdc2的表达在正常卵巢、卵巢上皮良性肿瘤及卵巢癌组织中呈明显递增趋势,且两者在卵巢癌组织中的表达显著高于其余2组,P均<0.01.plk1的表达与卵巢癌的组织学分级、临床分期及病理学类型无关;p34cdc2的阳性表达与卵巢癌的组织学分级、临床分期呈明显相关.在47倒卵巢癌组织中,plk1的表达与p34cdc2的表达呈正相关,r=0.388,P=0.004.结论:plkl和p340de2的高表达可能与卵巢癌的发生、发展密切相关,可望成为卵巢癌治疗的理想靶点.     

TOPK与肿瘤关系的研究进展

TOPK是一个新近发现的丝-苏氨酸蛋白激酶,是一个重要的信号分子.在生理情况下,TOPK仅表达于睾丸和胸腺中,与机体生殖细胞的成熟和免疫细胞激活有关.近年来研究显示,TOPK在多种恶性肿瘤细胞中呈高表达,不仅调控着肿瘤细胞的有丝分裂和细胞周期,并且参与了肿瘤细胞增殖、迁移、侵袭和凋亡过程.关于TOPK与肿瘤关系的研究正日益被人们关注,其特异性阻断剂也已被应用于肿瘤学研究中.     

Role of serine/threonine protein phosphatase 2A in cancer.

The serine/threonine protein phosphatase 2A (PP2A) appears to be critically involved in cellular growth control and potentially in the development of cancer. A few studies indicated that this enzyme might actually exert tumor suppressive function. However, other findings demonstrated the requirement for PP2A in cell growth and survival, which is not a characteristic of a typical tumor suppressor. This apparent discrepancy might be due to the fact that PP2A is a multitask enzyme system, rather than a single enzyme. Its individual subunits are encoded by a heterogeneous group of genes which give rise to a multitude of different PP2A holoenzyme complexes. Thus, the puzzling observation that PP2A exerts inhibitory, as well as stimulatory, effects on cell growth could be due to the activity of different PP2A complexes with distinct subcellular location and divers substrate specificity. At the same time, this abundance of PP2A components provides a large target for mutations that might derail proper enzyme function and could contribute to the process of tumorigenesis. So far, however, it has not been unequivocally established whether such mutations, examples of which have indeed been found in human cancer cells, result in the activation of an oncogenic function or rather in the inactivation of the presumed tumor suppressive role of PP2A. Therefore, the general opinion of PP2A as being a tumor suppressor needs to be viewed with caution.     

Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines

Most cases of human hepatocellular carcinoma develop after persistent chronic infection with human hepatitis B virus or hepatitis C virus, and host responses are presumed to have major roles in this process. To recapitulate this process, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. To identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis. Among the genes that were expressed differentially in the pre-malignant lesions, we focused on Pim-3, a member of a proto-oncogene Pim family, because its contribution to hepatocarcinogenesis remains unknown. Moreover, the unavailability of the nucleotide sequence of full-length human Pim-3 cDNA prompted us to clone it from the cDNA library constructed from a human hepatoma cell line, HepG2. The obtained 2,392 bp human Pim-3 cDNA encodes a predicted open reading frame consisting of 326 amino acids. Pim-3 mRNA was selectively expressed in human hepatoma cell lines, but not in normal liver tissues. Moreover, Pim-3 protein was detected in human hepatocellular carcinoma tissues and cell lines but not in normal hepatocytes. Furthermore, cell proliferation was attenuated and apoptosis was enhanced in human hepatoma cell lines by the ablation of Pim-3 gene with RNA interference. These observations suggest that aberrantly expressed Pim-3 can cause autonomous cell proliferation or prevent apoptosis in hepatoma cell lines.     

Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis

We previously observed that Pim-3 with serine/threonine kinase activity, was aberrantly expressed in malignant lesions of endoderm-derived organs, liver and pancreas. Because Pim-3 protein was not detected in normal colon mucosal tissues, we evaluated Pim-3 expression in malignant lesions of human colon, another endoderm-derived organ. Pim-3 was detected immunohistochemically in well-differentiated (43/68 cases) and moderately differentiated (23/41 cases) but not poorly differentiated colon adenocarcinomas (0/5 cases). Moreover, Pim-3 proteins were detected in adenoma (35/40 cases) and normal mucosa (26/111 cases), which are adjacent to adenocarcinoma. Pim-3 was constitutively expressed in SW480 cells and the transfection with Pim-3 short hairpin RNA promoted apoptosis. In the same cell line, a pro-apoptotic molecule, Bad, was phosphorylated at Ser(112) and Ser(136) sites of phosphorylation that are representative of its inactive form. Ser(112) but not Ser(136) phosphorylation in this cell line was abrogated by Pim-3 knockdown. Furthermore, in human colon cancer tissues, Pim-3 co-localized with Bad in all cases (9/9) and with phospho-Ser(112)Bad in most cases (6/9). These observations suggest that Pim-3 can inactivate Bad by phosphorylating its Ser(112) in human colon cancer cells and thus may prevent apoptosis and promote progression of human colon cancer.     

The mitotic serine/threonine kinase Aurora2/AIK is regulated by phosphorylation and degradation

Aurora2 is a cell cycle regulated serine/threonine protein kinase which is overexpressed in many tumor cell lines. We demonstrate that Aurora2 is regulated by phosphorylation in a cell cycle dependent manner. This phosphorylation occurs on a conserved residue, Threonine 288, within the activation loop of the catalytic domain of the kinase and results in a significant increase in the enzymatic activity. Threonine 288 resides within a consensus motif for the cAMP dependent kinase and can be phosphorylated by PKA in vitro. The protein phosphatase 1 is shown to dephosphorylate this site in vitro, and in vivo the phosphorylation of T288 is induced by okadaic acid treatment. Furthermore, we show that the Aurora2 kinase is regulated by proteasome dependent degradation and that Aurora2 phosphorylated on T288 may be targeted for degradation during mitosis. Our experiments suggest that phosphorylation of T288 is important for regulation of the Aurora2 kinase both for its activity and its stability.     

MicroRNA-184 inhibits neuroblastoma cell survival through targeting the serine/threonine kinase AKT2

Background

A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER)⁺ versus ER^- cancer.

Results

We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER⁺ tumors (p = 0.0059). In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p = 0.0062). Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015), but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain.

Conclusion

This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER⁺ luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER⁺ luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development.     

Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death

The hematopoietic cell S/T kinase Pim-1 was originally discovered as a target of murine leukemia provirus integration, and when expressed at increased levels is predisposing to lymphomagenesis. Recently, Pim-1 has been shown to enhance the activities of p100, c-Myb and cdc25a, and in part this might explain reported effects on mitogenesis. In the context of cytokine withdrawal, Pim-1 also can attenuate programmed cell death (PCD). Cytokine withdrawal, however, alters signaling pathways and can complicate the dissection of mitogenic vs apoptotic responses. To better study possible effects of Pim-1 on PCD, a hematopoietic cell model was developed in which proliferation was supported efficiently by SCF plus EPO in the absence of endogenous Pim-1 gene expression. This was provided by factor-dependent FDCW2 cells that express endogenous and functional c-Kit, and were transfected stably with truncated Epo receptor form mutated at a Y343 STAT5 binding site. In proliferating cells, exogenously expressed Pim-1 was observed to efficiently inhibit PCD as induced by either Co60 or adriamycin, and the dose-dependent nature of this effect was established in several independent clones. By comparison, effects of exogenous Pim-1 on mitogenesis were nominal. In addition, in cell fractionation studies an estimated 25% of Mr 34000 Pim-1 (but not Mr 44000 Pim-1) was present in nuclear extracts. Thus, Pim-1 efficiently buffers hematopoietic progenitor cells against death as induced by several clinically important apoptotic agents, and may directly target nuclear effectors.     

Ribozymes targeting serine/threonine kinase Akt1 sensitize cells to anticancer drugs

The serine/threonine kinase Akt is a key component of the cellular signaling pathway for survival and drug-resistance in cancer cells. In the present study we confirmed this view by expressing an antagonist of Akt, a dominant negative form of Akt, in HCT116 colon carcinoma cells and observing apoptosis induction in cells in which expression of the mutant protein had been induced. Three isoforms of Akt have been found: Akt1/PKBalpha, Akt2/PKBbeta and Akt3/PKBgamma. However, the function of individual isoforms with respect to tumorigenicity and drug-resistance of cancer cells is largely unknown. We designed ribozymes targeting the Akt1 protein in mammalian cells. Our data indicate that Akt1 ribozymes downregulate Akt1 expression to less than half that of control cells. Downregulation of Akt1 expression appears to sensitize HEK293 and HeLa cells to typical chemotherapeutic agents. However, Akt1 ribozymes had little effect on the proliferative activity of the cells. Thus, Akt as a whole and even just the Akt1 isozyme is an excellent target for chemotherapy. We further suggest a synergistic effect for combination therapy targeting Akt and other vital molecules such as tubulins, topoisomerases and protein kinases.