Pub Date : 2008-01-01DOI: 10.1101/087969824.51.237
Derrick J. Rossi, N. Sharpless
Long-lived metazoans must replace a variety of lost or consumed cells at a furious pace. For example, an adult human replaces about 1% of their 20 trillion red blood cells every day through de novo synthesis. Similarly staggering rates of cell division are at work to produce new cells in the gut, skin, and bone marrow throughout life. Additionally, certain tissues (e.g., memory lymphocytes and pancreatic β cells) possess a potential for facultative growth in the adult organism; i.e., under certain circumstances (e.g., viral infection and pregnancy), these normally quiescent cells can reenter the cell cycle to increase the mass of a given tissue through regulated proliferation. To offset the high cellular turnover rate in such tissues and avoid the onset of tissue-specific hypoplasia and atrophy, many mammalian tissues contain reservoirs of stem cells capable of generating terminally differentiated effector cell types. The unique cellular property that enables stem cells to maintain such function throughout is their ability to produce large numbers of differentiated cell types while also self-renewing themselves so that their reserves do not become depleted over time. Several lines of evidence—foremost of which is evidence indicating that aged tissues characteristically exhibit a diminished capacity to maintain homeostasis or return to homeostasis after exposure to stress—has implicated stem cell decline in the aging process. In this chapter, we review some of the evidence to support the notion that certain aspects of mammalian aging result from an age-dependent decline in the function of self-renewing stem cells, and...
{"title":"10 Aging in Mammalian Stem Cells and Other Self-renewing Compartments","authors":"Derrick J. Rossi, N. Sharpless","doi":"10.1101/087969824.51.237","DOIUrl":"https://doi.org/10.1101/087969824.51.237","url":null,"abstract":"Long-lived metazoans must replace a variety of lost or consumed cells at a furious pace. For example, an adult human replaces about 1% of their 20 trillion red blood cells every day through de novo synthesis. Similarly staggering rates of cell division are at work to produce new cells in the gut, skin, and bone marrow throughout life. Additionally, certain tissues (e.g., memory lymphocytes and pancreatic β cells) possess a potential for facultative growth in the adult organism; i.e., under certain circumstances (e.g., viral infection and pregnancy), these normally quiescent cells can reenter the cell cycle to increase the mass of a given tissue through regulated proliferation. To offset the high cellular turnover rate in such tissues and avoid the onset of tissue-specific hypoplasia and atrophy, many mammalian tissues contain reservoirs of stem cells capable of generating terminally differentiated effector cell types. The unique cellular property that enables stem cells to maintain such function throughout is their ability to produce large numbers of differentiated cell types while also self-renewing themselves so that their reserves do not become depleted over time. Several lines of evidence—foremost of which is evidence indicating that aged tissues characteristically exhibit a diminished capacity to maintain homeostasis or return to homeostasis after exposure to stress—has implicated stem cell decline in the aging process. In this chapter, we review some of the evidence to support the notion that certain aspects of mammalian aging result from an age-dependent decline in the function of self-renewing stem cells, and...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"29 1","pages":"237-265"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81994302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.1023
C. Arteaga, J. McPherson
The early publications of more than 20 years ago that described the discovery and characterization of the biological activities of TGF-β in vivo were prophetic in describing how TGF-β would ultimately serve as a therapeutic target for stimulating wound repair, preventing pathological fibrosis, and inhibiting tumor growth and metastasis (Roberts et al. 1980; Sporn et al. 1983). Since the discovery of TGF-β, other growth factors have also been identified as therapeutic targets, taken through product development, and ultimately commercialized. These have included platelet-derived growth factor (Regranex) for the treatment of diabetic foot ulcers, tumor necrosis factor antagonists (Remicade, Humira, and Enbrel) for the treatment of Crohn’s disease and rheumatoid arthritis, and a vascular endothelial growth factor (VEGF) antagonist (Avastin) for the treatment of cancer. An obvious question is why there have been no successful therapeutic agents developed based on TGF-β as a target, given the more than 20,000 papers that have been published on its important role in health and disease. Part of the answer is associated with the very complex biology of TGF-β in tissue homeostasis and the fact that it seems to be involved in numerous disease states. This biological complexity has provided a significant challenge for the scientists, clinicians, and business professionals in industry who have considered TGF-β as a therapeutic target but have struggled to determine how to develop it commercially. Another major concern has been the issue of potential toxicity associated with modulating TGF-β function in vivo. This concern was primarily based on targeted inactivation...
早在20多年前，早期发表的文章就描述了TGF-β在体内生物活性的发现和表征，预言了TGF-β最终将如何成为刺激伤口修复、防止病理性纤维化、抑制肿瘤生长和转移的治疗靶点(Roberts et al. 1980;Sporn et al. 1983)。自TGF-β发现以来，其他生长因子也被确定为治疗靶点，通过产品开发，最终实现商业化。其中包括用于治疗糖尿病足溃疡的血小板衍生生长因子(Regranex)，用于治疗克罗恩病和类风湿性关节炎的肿瘤坏死因子拮抗剂(Remicade、Humira和Enbrel)，以及用于治疗癌症的血管内皮生长因子(VEGF)拮抗剂(Avastin)。一个显而易见的问题是，鉴于已经发表了2万多篇关于TGF-β在健康和疾病中的重要作用的论文，为什么还没有成功开发出以TGF-β为靶点的治疗药物。部分答案与TGF-β在组织稳态中非常复杂的生物学特性以及它似乎与许多疾病状态有关的事实有关。这种生物复杂性给科学家、临床医生和行业内的商业专业人士带来了重大挑战，他们认为TGF-β是一种治疗靶点，但一直在努力确定如何将其商业化。另一个主要问题是体内调节TGF-β功能的潜在毒性问题。这种担忧主要是基于目标失活…
{"title":"32 Development of TGF-β-based Therapeutic Agents: Capitalizing on TGF-β’s Mechanisms of Action and Signal Transduction Pathways","authors":"C. Arteaga, J. McPherson","doi":"10.1101/087969752.50.1023","DOIUrl":"https://doi.org/10.1101/087969752.50.1023","url":null,"abstract":"The early publications of more than 20 years ago that described the discovery and characterization of the biological activities of TGF-β in vivo were prophetic in describing how TGF-β would ultimately serve as a therapeutic target for stimulating wound repair, preventing pathological fibrosis, and inhibiting tumor growth and metastasis (Roberts et al. 1980; Sporn et al. 1983). Since the discovery of TGF-β, other growth factors have also been identified as therapeutic targets, taken through product development, and ultimately commercialized. These have included platelet-derived growth factor (Regranex) for the treatment of diabetic foot ulcers, tumor necrosis factor antagonists (Remicade, Humira, and Enbrel) for the treatment of Crohn’s disease and rheumatoid arthritis, and a vascular endothelial growth factor (VEGF) antagonist (Avastin) for the treatment of cancer. An obvious question is why there have been no successful therapeutic agents developed based on TGF-β as a target, given the more than 20,000 papers that have been published on its important role in health and disease. Part of the answer is associated with the very complex biology of TGF-β in tissue homeostasis and the fact that it seems to be involved in numerous disease states. This biological complexity has provided a significant challenge for the scientists, clinicians, and business professionals in industry who have considered TGF-β as a therapeutic target but have struggled to determine how to develop it commercially. Another major concern has been the issue of potential toxicity associated with modulating TGF-β function in vivo. This concern was primarily based on targeted inactivation...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"21 1","pages":"1023-1061"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78685135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
New ideas pass through a series of stages from initial rejection to skepticism, to reluctant acceptance (without true belief in its importance), to a final casual acknowledgment of the obvious. It is fair to say that the acceptance of the idea that new neurons are generated in the adult brain of all mammals has been a slow process, and along the way, the idea has been met with skepticism and resistance. It is still not yet casually accepted as obvious. Rather, adult neurogenesis remains in the stage of reluctant acceptance, without a clear understanding of its importance, but the search for its function is in full gear. Joseph Altman’s original observations in the 1960s were met with significant reservation, as were attempted confirmations by a handful of investigators in the next 20 years. Somehow, Fernando Nottebohm and Steve Goldman’s observation of neurogenesis in the brains of adult canaries was received more positively but—because it took place in birds—was not considered as much of a threat to the prevailing belief (often even termed “dogma”) that there are no new neurons in the adult mammalian brain. Why this resistance to the capacity of the adult brain to generate new neurons? It was well accepted that other systems, like blood, liver, and skin, could generate new cells, so why not the brain? The most straightforward explanation is that the brain is not just any organ. At a philosophical and metaphysical level, the brain is thought to be the place where the...
{"title":"1 Adult Neurogenesis: A Prologue","authors":"F. Gage, Hongjun Song, G. Kempermann","doi":"10.1101/087969784.52.1","DOIUrl":"https://doi.org/10.1101/087969784.52.1","url":null,"abstract":"New ideas pass through a series of stages from initial rejection to skepticism, to reluctant acceptance (without true belief in its importance), to a final casual acknowledgment of the obvious. It is fair to say that the acceptance of the idea that new neurons are generated in the adult brain of all mammals has been a slow process, and along the way, the idea has been met with skepticism and resistance. It is still not yet casually accepted as obvious. Rather, adult neurogenesis remains in the stage of reluctant acceptance, without a clear understanding of its importance, but the search for its function is in full gear. Joseph Altman’s original observations in the 1960s were met with significant reservation, as were attempted confirmations by a handful of investigators in the next 20 years. Somehow, Fernando Nottebohm and Steve Goldman’s observation of neurogenesis in the brains of adult canaries was received more positively but—because it took place in birds—was not considered as much of a threat to the prevailing belief (often even termed “dogma”) that there are no new neurons in the adult mammalian brain. Why this resistance to the capacity of the adult brain to generate new neurons? It was well accepted that other systems, like blood, liver, and skin, could generate new cells, so why not the brain? The most straightforward explanation is that the brain is not just any organ. At a philosophical and metaphysical level, the brain is thought to be the place where the...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"114 1","pages":"1-5"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88074610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.461
Shigeto Miura, M. Whitman, Y. Mishina
Upon implantation at embryonic day 4.5 (E4.5), the mouse embryo, a blastocyst, initiates the formation of the egg cylinder. During this process, the inner cell mass, located at the embryonic side of the blastocyst, differentiates into the epiblast and the visceral endoderm. On the opposite (abembryonic) side of the blastocyst, the mural trophoectoderm differentiates into the extraembryonic ectoderm, forming a radially symmetric structure by E5.5 (Fig. 1a,b). The future fetus is derived entirely from the epiblast. The visceral endoderm and extraembryonic ectoderm will contribute only to extraembryonic structures such as the future placenta. At the time of implantation, the early embryo is most clearly defined by this embryonic–abembryonic axis. The first sign of overt morphological asymmetry in the embryo begins with the formation of the anterior visceral endoderm, an extraembryonic tissue, at E5.5. The anterior visceral endoderm first appears at the distal tip of the egg cylinder and is defined by molecular markers such as expression of Hex . This distal region of the visceral endoderm starts to move toward the future anterior side at E5.5, and by E5.75–6.0, the distal visceral endodermal cells are located at the future anterior side of the embryo to form the anterior visceral endoderm (Rivera-Perez et al. 2003; Srinivas et al. 2004). Although the formation and anterior movement of the anterior visceral endoderm have long been thought to mark the initiation of anterior–posterior axis formation, recent findings have identified molecular asymmetries along the prospective anterior–posterior axis before the movement of the...
在胚胎第4.5天(E4.5)植入后，小鼠胚胎(囊胚)开始形成卵筒。在此过程中，位于胚泡胚胎侧的内细胞群分化为外胚层和内脏内胚层。在囊胚的对面(胚胎外)，壁滋养外胚层分化为胚胎外胚层，通过E5.5形成径向对称结构(图1a,b)。未来的胎儿完全来自外胚层。内脏内胚层和胚胎外胚层只会形成胚胎外结构，如未来的胎盘。在着床时，早期胚胎最清楚地由胚胎-胚胎外轴界定。胚胎明显形态不对称的第一个迹象开始于胚胎前内脏内胚层的形成，胚胎外组织，在E5.5。前内脏内胚层首先出现在卵筒的远端，并由分子标记(如Hex的表达)来定义。在E5.5时，远端内脏内胚层开始向未来前部移动，到E5.75-6.0时，远端内脏内胚层细胞位于胚胎的未来前部，形成前内脏内胚层(Rivera-Perez et al. 2003;Srinivas et al. 2004)。尽管内脏前内胚层的形成和前向运动长期以来被认为标志着前后轴形成的开始，但最近的研究发现，在前-后轴运动之前，沿着预期的前后轴的分子不对称。
{"title":"16 TGF-β Family Signaling in Early Postimplantation Development of the Mouse","authors":"Shigeto Miura, M. Whitman, Y. Mishina","doi":"10.1101/087969752.50.461","DOIUrl":"https://doi.org/10.1101/087969752.50.461","url":null,"abstract":"Upon implantation at embryonic day 4.5 (E4.5), the mouse embryo, a blastocyst, initiates the formation of the egg cylinder. During this process, the inner cell mass, located at the embryonic side of the blastocyst, differentiates into the epiblast and the visceral endoderm. On the opposite (abembryonic) side of the blastocyst, the mural trophoectoderm differentiates into the extraembryonic ectoderm, forming a radially symmetric structure by E5.5 (Fig. 1a,b). The future fetus is derived entirely from the epiblast. The visceral endoderm and extraembryonic ectoderm will contribute only to extraembryonic structures such as the future placenta. At the time of implantation, the early embryo is most clearly defined by this embryonic–abembryonic axis. The first sign of overt morphological asymmetry in the embryo begins with the formation of the anterior visceral endoderm, an extraembryonic tissue, at E5.5. The anterior visceral endoderm first appears at the distal tip of the egg cylinder and is defined by molecular markers such as expression of Hex . This distal region of the visceral endoderm starts to move toward the future anterior side at E5.5, and by E5.75–6.0, the distal visceral endodermal cells are located at the future anterior side of the embryo to form the anterior visceral endoderm (Rivera-Perez et al. 2003; Srinivas et al. 2004). Although the formation and anterior movement of the anterior visceral endoderm have long been thought to mark the initiation of anterior–posterior axis formation, recent findings have identified molecular asymmetries along the prospective anterior–posterior axis before the movement of the...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"1 1","pages":"461-491"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90399785","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.259
C. Heldin
Binding of transforming growth factor-β (TGF-β) family members to their heteromeric complexes of type I and type II serine-threonine kinase receptors makes it possible for the type II receptor to phosphorylate and activate the type I receptor (see Chapter 6). Although several substrates for the type I receptor kinases have been identified, the most important ones for the transmission of the intracellular signals are members of the Smad family of signal transducers. The receptor-activated (R-) Smads (Smad1, Smad5, and Smad8, for bone morphogenic proteins [BMPs] and Smad2 and 3 for TGF-βs and activins) are phosphorylated by the type I receptors and then form hetero-oligomeric complexes with the common mediator (co-) Smad (only one co-Smad in humans, Smad4), which are translocated to the nucleus where they regulate the transcription of specific genes. The third Smad subfamily is represented by the inhibitory (I-) Smads, that is, Smad6 and Smad7, which, on the one hand, inhibit signaling via heteromeric serine-threonine kinase receptor complexes in a feedback mechanism and, on the other hand, promote certain non-Smad signaling pathways. The inhibitory Smads are discussed in Chapter 12 and are not covered in this chapter. The aim of this chapter is to review the mechanism whereby Smads are activated by receptors, how they are translocated to the nucleus, and how their activities are modulated by posttranslational modifications. The role of Smad complexes as transcriptional regulators in the nucleus is not discussed here (see Chapter 10). THE SMAD FAMILY Discovery of the Smads The Smad family was...
{"title":"9 TGF-β Signaling from Receptors to Smads","authors":"C. Heldin","doi":"10.1101/087969752.50.259","DOIUrl":"https://doi.org/10.1101/087969752.50.259","url":null,"abstract":"Binding of transforming growth factor-β (TGF-β) family members to their heteromeric complexes of type I and type II serine-threonine kinase receptors makes it possible for the type II receptor to phosphorylate and activate the type I receptor (see Chapter 6). Although several substrates for the type I receptor kinases have been identified, the most important ones for the transmission of the intracellular signals are members of the Smad family of signal transducers. The receptor-activated (R-) Smads (Smad1, Smad5, and Smad8, for bone morphogenic proteins [BMPs] and Smad2 and 3 for TGF-βs and activins) are phosphorylated by the type I receptors and then form hetero-oligomeric complexes with the common mediator (co-) Smad (only one co-Smad in humans, Smad4), which are translocated to the nucleus where they regulate the transcription of specific genes. The third Smad subfamily is represented by the inhibitory (I-) Smads, that is, Smad6 and Smad7, which, on the one hand, inhibit signaling via heteromeric serine-threonine kinase receptor complexes in a feedback mechanism and, on the other hand, promote certain non-Smad signaling pathways. The inhibitory Smads are discussed in Chapter 12 and are not covered in this chapter. The aim of this chapter is to review the mechanism whereby Smads are activated by receptors, how they are translocated to the nucleus, and how their activities are modulated by posttranslational modifications. The role of Smad complexes as transcriptional regulators in the nucleus is not discussed here (see Chapter 10). THE SMAD FAMILY Discovery of the Smads The Smad family was...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"34 1","pages":"259-285"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85058039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.493
George Pyrowolakis, B. Hartmann, M. Affolter
In this chapter, we first introduce the general components of the different transforming growth factor-β (TGF-β) family signaling pathways that have been identified in Drosophila . We then describe at which steps and how the signaling pathways are regulated at different developmental stages. We highlight two topics—extracellular ligand distribution and nuclear readout of distinct levels of signaling—in which Drosophila work has provided unique insight in the past decade. For several reviews that discuss other aspects of TGF-β family signaling in Drosophila in more detail, see Affolter et al. (2001), Parker et al. (2004), and Raftery and Sutherland (1999). CORE EFFECTORS OF THE TGF-β FAMILY SIGNALING PATHWAYS IN DROSOPHILA The core components of TGF-β family signaling pathways in Drosophila show a high degree of conservation at the sequence as well as at the functional level with regard to their vertebrate counterparts, that is, the bone morphogenetic protein- (BMP) and activin-signaling pathways. In fact, several genes encoding Drosophila TGF-β family ligands or receptors were identified using polymerase chain reaction (PCR) approaches or by DNA sequence data mining starting from the sequences for mammalian members of the signaling pathway. The number of ligands and receptors encoded by the Drosophila genome is lower than that in vertebrates; seven ligand and five receptor-encoding genes have been identified (Fig. 1) (Parker et al. 2004). Three of the seven ligands, Decapentaplegic (Dpp), Screw (Scw), and Glass bottom boat (Gbb; formerly termed 60A), belong to the subfamily of BMPs, whereas dActivin and Dawdle (Daw) are related to...
在本章中，我们首先介绍了在果蝇中发现的不同转化生长因子-β (TGF-β)家族信号通路的一般成分。然后，我们描述了在哪些步骤和如何在不同的发育阶段调节信号通路。我们强调两个主题-细胞外配体分布和不同水平信号的核读出-在果蝇的工作中提供了独特的见解在过去的十年中。关于更详细地讨论果蝇中TGF-β家族信号传导的其他方面的几篇综述，请参见Affolter et al.(2001)、Parker et al.(2004)和ratry and Sutherland(1999)。果蝇TGF-β家族信号通路的核心效应因子果蝇TGF-β家族信号通路的核心成分在序列和功能水平上与脊椎动物的对应体骨形态发生蛋白(BMP)和激活素信号通路具有高度的保守性。事实上，利用聚合酶链反应(PCR)方法或从哺乳动物信号通路成员序列开始的DNA序列数据挖掘，已经鉴定出了几个编码果蝇TGF-β家族配体或受体的基因。果蝇基因组编码的配体和受体数量低于脊椎动物;已经鉴定出7个配体和5个受体编码基因(图1)(Parker et al. 2004)。七种配体中的三种，Decapentaplegic (Dpp)、Screw (Scw)和Glass bottom boat (Gbb);以前称为60A)，属于bmp亚家族，而dActivin和Dawdle (Daw)与…
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Pub Date : 2008-01-01DOI: 10.1101/087969752.50.889
W. Grady, S. Markowitz
Transforming growth factor β (TGF-β) is the prototype member of a family of secreted proteins that include the three TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3), activins, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs), inhibins, nodal, and anti-Mullerian hormone. These ligands all mediate biological activities in cells through binding to heteromeric receptor complexes at the cell surface that are composed of type I and type II receptors. The TGF-β family has been the subject of intense investigation since its discovery, and these studies have revealed roles for TGF-β signaling in development and cancer biology. In epithelial cells, TGF-β inhibits cell proliferation, induces apoptosis, and mediates differentiation, which suggests that this pathway has tumor-suppressor activities in epithelial tumors. Accordingly, a large body of evidence has established that elements of the TGF-β signaling pathway have a prominent role as tumor-suppressor genes in neoplasms originating from epithelial tissues, particularly gastrointestinal tract cancers. Conversely, other studies provide evidence that in certain contexts, TGF-β promotes the invasive or metastatic behavior of established cancer cells, suggesting that TGF-β paradoxically can have opposing roles in human cancers that appear to depend on the stage of the cancer. This chapter focuses on the tumor-suppressor activity of the TGF-β signaling pathway with an emphasis on the deregulation of TGF-β signaling in gastrointestinal malignancies, the organ system in which tumor-suppressor effects have been most clearly demonstrated. OVERVIEW OF TGF-β SIGNALING PATHWAY ELEMENTS AND ROLE IN TUMOR SUPPRESSION TGF-β is a multifunctional cytokine that induces growth inhibition, apoptosis, and differentiation...
{"title":"28 TGF-β Signaling Pathway and Tumor Suppression","authors":"W. Grady, S. Markowitz","doi":"10.1101/087969752.50.889","DOIUrl":"https://doi.org/10.1101/087969752.50.889","url":null,"abstract":"Transforming growth factor β (TGF-β) is the prototype member of a family of secreted proteins that include the three TGF-β isoforms (TGF-β1, TGF-β2, and TGF-β3), activins, growth and differentiation factors (GDFs), bone morphogenetic proteins (BMPs), inhibins, nodal, and anti-Mullerian hormone. These ligands all mediate biological activities in cells through binding to heteromeric receptor complexes at the cell surface that are composed of type I and type II receptors. The TGF-β family has been the subject of intense investigation since its discovery, and these studies have revealed roles for TGF-β signaling in development and cancer biology. In epithelial cells, TGF-β inhibits cell proliferation, induces apoptosis, and mediates differentiation, which suggests that this pathway has tumor-suppressor activities in epithelial tumors. Accordingly, a large body of evidence has established that elements of the TGF-β signaling pathway have a prominent role as tumor-suppressor genes in neoplasms originating from epithelial tissues, particularly gastrointestinal tract cancers. Conversely, other studies provide evidence that in certain contexts, TGF-β promotes the invasive or metastatic behavior of established cancer cells, suggesting that TGF-β paradoxically can have opposing roles in human cancers that appear to depend on the stage of the cancer. This chapter focuses on the tumor-suppressor activity of the TGF-β signaling pathway with an emphasis on the deregulation of TGF-β signaling in gastrointestinal malignancies, the organ system in which tumor-suppressor effects have been most clearly demonstrated. OVERVIEW OF TGF-β SIGNALING PATHWAY ELEMENTS AND ROLE IN TUMOR SUPPRESSION TGF-β is a multifunctional cytokine that induces growth inhibition, apoptosis, and differentiation...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"51 2 1","pages":"889-937"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90287019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.761
M. Goumans, Rita L. C. Carvalho, C. Mummery, P. Dijke
Genetic studies in model organisms and humans have revealed pivotal roles for transforming growth factor-β (TGF-β) family members in cardiovascular development and maintenance. In vitro studies demonstrate that some TGF-β family members, signaling via their type I and type II receptors (Chapter 6) and intracellular Smads (Chapter 9), potently regulate the proliferation, differentiation, and migration of endothelial cells that line the entire vasculature and mural cells (vascular smooth muscle cells and pericytes) that surround the endothelial cells and aid in processes such as contraction. However, the context-dependent activities of TGF-β family members and their interactions with many cell types other than vascular cells, for example, epithelial and immune cells, have made the in vivo interpretation of the roles of TGF-β family members in vascular biology difficult. Here, we review the roles of TGF-β family members in cardiovascular development and function, and we discuss a model in which TGF-β signals via two distinct type I receptors in vascular cells. These receptors are the broadly expressed TGF-β type I receptor (TβRI, also termed ALK-5) acting via Smad2 and Smad3, and, the endothelial cell-restricted ALK-1 acting via Smad1 and Smad5. The roles of TGF-β family receptors in the development of hereditary hemorrhagic telangiectasia (HHT), primary pulmonary hypertension, and Marfan and Loeys-Dietz syndromes are also discussed. CARDIOVASCULAR DEVELOPMENT Vasculogenesis and Angiogenesis The first functional organ system to form in the embryo is the cardiovascular system. Shortly after gastrulation, when cells from the epiblast invaginate to become mesoderm, a vascular plexus develops in the visceral...
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As research on postnatal neuronal progenitor, precursor, and stem cells progresses, methods of increasing sensitivity and complexity will be brought to bear in revealing how these cell types are maintained in the adult brain and how the brain adds neurons to mature circuits. Here, we review historical and current methods, such as bromodeoxyuridine (BrdU) labeling, and discuss several emerging genetic techniques, including viral vectors, small interfering RNAs (siRNAs), and inducible transgenic/knockout mice, that will be useful for the labeling and/or mutation of adult neuronal precursor cells (NPCs). As the complexity of these methods increases, so does the potential for misinterpretation of the results. The realization must be made that all methods have inherent disadvantages and confounds, preventing conclusive and definitive interpretations if used without cross-validation. We hope to give insight into how pitfalls might be avoided and provide a primer on additional methods that might be used in the pursuit of definitive results. In the past decade, a newfound appreciation has developed for the regions displaying neurogenesis in the adult mammal (Gage 2000; Lledo et al. 2006). In two regions, the dentate gyrus (DG) of the hippocampus and the olfactory bulb (OB), neurons are continually added after birth (Lois and Alvarez-Buylla 1994; Kuhn et al. 1996). In the hippocampus, neurons are born in the subgranular zone (SGZ) from Gfap + precursor cells and migrate a short distance into the granule cell layer (GCL), where they integrate, sending an axon to CA3 and receiving input at their apical dendrite (Seri et al...
随着对出生后神经元祖细胞、前体细胞和干细胞研究的进展，越来越敏感和复杂的方法将有助于揭示这些细胞类型如何在成人大脑中维持，以及大脑如何将神经元添加到成熟回路中。在这里，我们回顾了历史和当前的方法，如溴脱氧尿苷(BrdU)标记，并讨论了几种新兴的遗传技术，包括病毒载体、小干扰rna (sirna)和可诱导的转基因/敲除小鼠，这些技术将有助于标记和/或突变成人神经元前体细胞(npc)。随着这些方法的复杂性增加，结果被误解的可能性也在增加。必须认识到，所有的方法都有固有的缺点和混乱，如果没有交叉验证，就会阻止结论性和明确的解释。我们希望深入了解如何避免陷阱，并提供可能用于追求明确结果的其他方法的入门。在过去的十年中，对成年哺乳动物中显示神经发生的区域有了新的认识(Gage 2000;Lledo et al. 2006)。在海马齿状回(DG)和嗅球(OB)两个区域，神经元在出生后不断增加(Lois and Alvarez-Buylla 1994;Kuhn et al. 1996)。在海马体中，神经元从Gfap +前体细胞的亚颗粒区(SGZ)中诞生，并向颗粒细胞层(GCL)迁移一小段距离，在那里它们整合，向CA3发送轴突，并在顶端树突接受输入(Seri等人)。
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Pub Date : 2008-01-01DOI: 10.1101/087969752.50.121
T. Katagiri, T. Suda, K. Miyazono
Bone morphogenetic proteins (BMPs) have critical roles in skeletal development by regulating the proliferation, differentiation, and apoptosis of many types of cells. Molecular cloning of BMPs and identification of molecules homologous to them have shed light on the novel functions of BMPs in vertebrates as well as in invertebrates, including Drosophila and nematodes. In this chapter, we describe biochemical properties and biological activities of BMPs; we focus, in particular, on the cell differentiation induced by BMPs. Although BMPs are now known to be multifunctional factors in vertebrates and invertebrates, they were originally discovered and identified as a bone-inducing activity in bone matrix in 1965. Marshall R. Urist (1965) first prepared demineralized bone by treating bone with hydrochloric acid and then implanting the demineralized bone in muscular tissues. A few weeks after transplantation, he found that new cartilage and bone tissues with bone marrow had been ectopically formed in muscular tissue (Urist 1965). These findings clearly indicated that the demineralized bone matrix contained unknown bioactive substance(s) capable of inducing differentiation of bone-forming cells in muscular tissues. This ectopic bone-inducing activity was subsequently named “bone morphogenetic protein,” because it disappeared after trypsin digestion (Urist and Strates 1971). However, all attempts to isolate and identify BMP were unsuccessful for more than 20 years after Urist’s original findings because of the difficulty in isolating BMP from bone matrix. BMP activity was water insoluble and could be extracted from demineralized bone matrix with protein denaturants (Urist and Strates 1971; Sampath and Reddi 1981; Yoshikawa et...
骨形态发生蛋白(BMPs)通过调节多种细胞的增殖、分化和凋亡，在骨骼发育中起着至关重要的作用。bmp的分子克隆和同源分子的鉴定揭示了bmp在脊椎动物和无脊椎动物(包括果蝇和线虫)中的新功能。在本章中，我们描述了bmp的生化特性和生物活性;我们特别关注bmp诱导的细胞分化。虽然bmp现在被认为是脊椎动物和无脊椎动物的多功能因子，但它们最初是在1965年发现并确定为骨基质中的骨诱导活性。Marshall R. Urist(1965)首先用盐酸处理骨，然后将脱矿骨植入肌肉组织，制备脱矿骨。移植几周后，他发现肌肉组织中异位形成了新的带有骨髓的软骨和骨组织(Urist 1965)。这些发现清楚地表明，脱矿骨基质中含有未知的生物活性物质，能够诱导肌肉组织中骨形成细胞的分化。这种异位骨诱导活性后来被命名为“骨形态发生蛋白”，因为它在胰蛋白酶消化后消失了(Urist和Strates, 1971)。然而，在Urist最初的发现之后的20多年里，所有分离和鉴定BMP的尝试都没有成功，因为从骨基质中分离BMP很困难。BMP的活性是不溶于水的，可以用蛋白质变性剂从脱矿骨基质中提取(Urist and Strates 1971;Sampath and Reddi 1981;Yoshikawa等……
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