Role of the retinoblastoma tumor suppressor protein in cellular differentiation

The retinoblastoma protein (pRb105) is a true tumor suppressor as deregulation of the Rb pathway by either mutation of pRb105 itself or other proteins in the pathway, such as p16INK4a, occur in most cancers. This prototypical family member, along with the related p107 and p130, are involved in the control of cell cycle regulation, but pRb105 has also been shown to be involved in tissue development and differentiation. This prospective will discuss the increasing evidence for a role of pRb105 in cellular differentiation and the fact that various cancers, which contain mutant pRb105, or mutations in proteins in the pRb105 pathway, are perhaps a result of deregulation of differentiation.     

Role of the immediate early response 3 (IER3) gene in cellular stress response, inflammation and tumorigenesis

The expression of the early response gene immediate early response 3 (IER3), formerly known as IEX-1, is induced by a great variety of stimuli, such as growth factors, cytokines, ionizing radiation, viral infection and other types of cellular stress. Being of a rather unique protein structure not sharing any similarity to other vertebrate proteins, IER3 plays a complex and to some extent contradictory role in cell cycle control and apoptosis. As outlined in this review, these effects of IER3 relate to an interference with certain signalling pathways, in particular NF-κB, MAPK/ERK and PI3K/Akt. In addition to numerous functional data relying on cell culture based studies, transgenic and knock-out mouse models revealed an involvement of IER3 expression in immune functions and in the physiology of the cardiovascular system. Deficiency of IER3 expression in mice results in an aberrant immune regulation and enhanced inflammation, in an alteration of blood pressure control and hypertension or in an impaired genomic stability. A number of patient related studies revealed an involvement of IER3 in tumorigenesis in a cell-type dependent but not yet understood manner. Future studies should establish the potential of IER3 as a new predictive marker and as a molecular target in human diseases such as cancer, inflammatory diseases or hypertension.     

Metabolism,cellular actions,and cytotoxicity of selenomethionine in cultured cells

Selenomethionine metabolism and the biochemical basis for its cytotoxicity were analyzed in cultured human and murine lymphoid cells. The metabolic pathways were also addressed, using purified mammalian enzymes and crude tissue extracts. Selenomethionine was found to be effectively metabolized to S-adenosylmethionine analog, and that analog was further metabolized in transmethylation reactions and in polyamine synthesis, similarly to the corresponding sulphur metabolites of methionine. Selenomethionine did not block these pathways, nor was there a specific block on the synthesis of DNA, RNA, or proteins when added to the culture medium. Selenomethionine showed cytotoxicity at above 40 microM levels. Yet, low selenomethionine levels (10 microM) could replace methionine and support cell growth in the absence of methionine. Selenomethionine toxicity took place concomitantly with changes in S-adenosylmethionine pools. D-form was less cytotoxic than L-form. Methionine concentration modified the cytotoxicity. Together, this indicates that selenomethionine uptake and enzymic metabolism are involved in the cytotoxicity in a yet unknown way.     

The role of cholinesterases in chagas disease

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) hydrolyze acetylcholine (ACh) in neural synaptic clefts and are primarily found in erythrocytes and blood plasma, respectively. Besides inactivating ACh, cholinesterases may play a non-classical role in inflammation and in immune response. In a previous study, we reported that BChE levels were decreased in chronic Chagas disease patients presenting the mega syndromes. In this series, we reported that: i) the activity of AChE did not differ between patients and controls, irrespective of the presence or not of the 1057C > A ACHE polymorphism, and ii) the increased BChE levels modestly influenced the AChE activity in Chagas disease.     

Conformational changes and disease - serpins, prions and Alzheimer''s

Some of the most perplexing disorders in medicine are each now known to arise from the conformational instability of an underlying protein. The consequence is a continuum of pathologies with typically a change in fold leading to ordered aggregation and tissue deposition. The serpins provide a structural prototype for these pathologies and give a perspective on the assessment of current proposals as to the conformational basis of both Alzheimer's disease and the transmissible prion encephalopathies.     

Role of Ribonuclease and Ribonuclease Inhibitor Activities in Alzheimer''s Disease

It has been suggested that defects in the relationship between ribonuclease and its proteinaceous inhibitor could be a contributory factor in Alzheimer's disease. We have investigated this possibility further by analysing free and bound enzyme activities and the activity of the inhibitor in nine regions of diseased and normal brain. These were chosen to include areas known to be affected by the disease, regions not histologically affected but thought to be involved in the disease process, and areas not thought to be involved in the disease. Neither the enzyme nor its inhibitor is defective in its activities in the chosen areas of Alzheimer's disease brain when compared with those of carefully age-matched controls.     

Non-classical androgenic actions of RU38486 in androgen-responsive Shionogi carcinoma 115 cells in serum-free culture

Antiglucocorticoid and antiprogestin RU38486 (RU486) stimulated the growth of highly androgen- and moderately glucocorticoid-sensitive SC-3 cells (a cloned cell line from Shionogi mouse mammary carcinoma 115) in a dose-dependent manner. A maximal 8-fold stimulation of growth by RU486 has been observed at 10(-7) M in a serum-free medium and its potency has been found to be almost the same as that of dexamethasone (Dex). The growth rate of SC-3 cells treated by triamcinolone acetonide (TA) or Dex combined with RU486 at 10(-9)-10(-7) M was enhanced compared to cells treated by TA or Dex alone, indicating that RU486 had additive rather than antagonistic effects. Our previous study revealed that RU486 could compete with the specific uptake of [3H]testosterone in intact SC-3 cells at relatively low affinity and the present study showed that the stimulatory effect of RU486 on the growth of SC-3 cells was significantly inhibited by pure antiandrogen flutamine and that half-maximal inhibition by flutamine was achieved at 10(-6) M. Moreover, we demonstrated that the conditioned medium from RU486-stimulated SC-3 cells contained growth-promoting activity which caused a 3.5-fold increase in DNA synthesis by SC-3 cells in the absence of RU486 and which was abolished by treatment with heparin-Sepharose. These results indicate that RU486-induced growth of SC-3 cells may be expressed as an androgenic activity through androgen receptor and mediated by a heparin-binding growth factor.     

Role of CAGE, a novel cancer/testis antigen, in various cellular processes, including tumorigenesis, cytolytic T lymphocyte induction, and cell motility

A cancer-associated antigen gene (CAGE) was identified by serological analysis of a recombinant cDNA expression library (SEREX). The gene was identified by screening cDNA expression libraries of human testis and gastric cancer cell lines with sera from patients with gastric cancer. CAGE was found to contain a D-E-A-D box domain and encodes a putative protein of 630 amino acids with possible helicase activity. The CAGE gene is widely expressed in various cancer tissues and cancer cell lines. Demethylation plays a role in the activation of CAGE in certain cancer cell lines where the gene is not expressed. The functional roles of CAGE in tumorigenesis, the molecular mechanisms of CAGE expression, and cell motility are also discussed.     

乙酰胆碱酯酶的非经典功能及其与A1zheimer's疾病的关系

乙酰胆碱酯酶（acetylcholinesterase,AChE)是主要存在于神经系统的一种水解酶,其经典功能是水解神经递质乙酰胆碱,从而终止神经冲动的传递。但是近年来,研究者发现许多证据表明它具有“非经典”的新功能,引起了人们的关注。除了水解神经递质乙酰胆碱的经典功能外,AChE对神经细胞的分化、迁移,突触的形成,造血系细胞和肿瘤细胞的增殖与分化调控也有作用。最近的研究结果显示：AChE可能在细胞凋亡过程中起重要作用,这对于认识Alzheimer‘s疾病（AD）的发病机理又有新的进步。     

APC dosage effects in tumorigenesis and stem cell differentiation

It is well established that concentration gradients of signaling molecules (the so-called "morphogens") organize and pattern tissues in developing animals. In particular, studies in Drosophila and different vertebrates have shown that gradients of the Wnt, Hedgehog (Hh) and transforming growth factor-beta (TGF-beta) families of morphogens play critical roles in limb patterning. Morphogens are often expressed in organizing centres and can act over a long range to coordinate the patterning of an entire field of cells. These observations imply that exposure to different concentrations of these diffusible factors may trigger differential cellular responses. In order to study these dosage-dependent Wnt/beta-catenin signaling effects, we have generated several hypomorphic mutant alleles at the mouse Apc locus and studied their cellular and phenotypic outcomes in stem cell renewal and differentiation, and in tumorigenesis. The results clearly show that Apc mutations differentially affect the capacity of stem cells to differentiate in a dosage-dependent fashion. Likewise, different Apc mutations (and the corresponding Wnt signaling dosages) confer different degrees of susceptibility to tumorigenesis in the corresponding mouse models. These results have implications for the understanding of the molecular and cellular basis of tumor initiation by defects in the Wnt pathway. We propose a model in which adult somatic stem cell compartments are characterized by tissue-specific beta-catenin threshold levels for cell proliferation, differentiation and apoptosis. Different APC mutations will result in different levels of beta-catenin signaling, thus conferring different degrees of tumor susceptibility in different tissues. Hence, beta-catenin dosage-dependent effects may not only explain how a single pathway is involved in the development and homeostasis of different tissues, but also its pleiotrophic role in tumorigenesis.     

Role of toll-like receptors in tissue repair and tumorigenesis

Toll-like receptors (TLRs) play a critical role in host defense from microbial infection. TLRs recognize conserved molecular structures produced by microorganisms and induce activation of innate and adaptive immune responses. The inflammatory responses induced by TLRs play an important role TLRs not only in host defense from infection, but also in tissue repair and regeneration. This latter function of TLRs can also contribute to tumorigenesis. Here we review recent progress in understanding the role of TLRs in cancer development.     

Alzheimer''s disease: Transgenic models to test new chemicals and pharmaceuticals

Alzheimer's disease is the most common form of senile dementia and is predicted to become even more prevalent as the proportion of elderly in the population increases over the next few decades. As yet, there are no effective treatments for the disorder. A major limitation to identifying new drugs and therapeutic targets for Alzheimer's disease has been the absence of an animal model displaying typical Alzheimer's pathology. Transgenic technology is now providing a powerful new approach for the development of animal models of Alzheimer's disease.     

干细胞的异常分化与肿瘤发生

干细胞是一类具有自我更新和多向分化潜能的细胞群体。越来越多的研究表明,干细胞异常分化可导致肿瘤。并且在肿瘤组织中存在部分细胞,它们具有干细胞的多种特性,被称为肿瘤干细胞(cancer stem cell,CSC)。肿瘤干细胞理论的提出,为肿瘤的治疗与研究提供了新的方向。本文综述了正常干细胞异常分化、肿瘤干细胞的存在和特性、肿瘤干细胞靶向治疗的前景及所面临的问题等方面的研究进展。