Cytokine Regulation of Normal and Neoplastic Hematopoietic Cell Growth

在造血过程中，需要不断产生大量成熟的细胞， 从少量的干细胞中分离出八种不同的谱系需要一系列高度复杂的 事件造血干细胞（HSC），可以保持静止数月，必须保持其功能。 分化成所有谱系、自我更新和长期繁殖的能力 骨髓（LTRA）。许多控制造血的关键相互作用受到以下因素的调节： 可溶性或细胞外介质，其可以具有重叠的、相加的和/或相反的 在给定的细胞类型上起作用。转化生长因子β 1（TGF-β 1）是其中之一。 由于我们的体外和体内研究表明，TGF-β是造血的关键调节因子， 是造血各个阶段的调节器目前的一个优先事项是进一步界定 TGF-β的生理相关性，并确定其发挥其各种作用的机制。 复杂的影响。重要的问题仍有待回答。是多效性效应 TGF-β对细胞内介质Smad 2和Smad 3的不同作用引起的造血作用， 或与其他信号转导途径的串扰？什么是相对贡献 自分泌和旁分泌TGF-β在HSC调节中的作用细胞内TGF-β信号的改变 改变差异化结果？我们已经发现，TGF-β 1调节HSC的静止， 通过自分泌和旁分泌机制存活。此外，中和自分泌 HSC中的TGF-β导致更快的植入，骨髓需要的细胞更少 移植与此相反，在人HSC中，在存在TGF-b的情况下， 干细胞因子刺激红系祖细胞的产生， 促红细胞生成素明确自分泌TGF-β调节HSC的作用机制， 提供了新的治疗机会。此外，我们还发现Smad 2/3是 细胞内传感器，其调节响应于 药物制剂。全反式维甲酸（ATRA）刺激粒细胞分化 通过刺激磷酸酶活性使Smad 2/3脱磷酸化;而维生素D3 通过Smad 2/3的磷酸化刺激单核细胞分化。此外，本发明还提供了一种方法， MAPK信号通路和Smad通路的不同成员之间的串扰改变了 髓系和红系分化的结果。此外，我们还证明了Smad 2 Smad 3对早期造血功能有不同的影响。因此， 特异性信号对造血结果具有深远的影响。由于TGF-β的改变， 其受体和下游效应物（SMAD）都与肿瘤发生有关， 这些研究可以提供对恶性过程的深入了解。TGF-β 1抑制增殖 通过限制通过细胞周期的G1期，部分地通过快速 基因的转录激活，如细胞周期抑制剂。我们最近发现 结核菌素硬化基因产物2，另一种肿瘤抑制基因，导致生长停滞， G1直接与Smad 2相互作用，这是一种由TGF-β介导的转录激活（手稿 出版中）。此外，我们已经表明，块茎素是一个强大的刺激剂TGF-β 1调节， 转录和分化事件。因此，功能的丧失 块茎素和/或Smads可导致不受控制的细胞增殖， 分化因此，TGF-β 1调节的微妙而慢性的变化可导致 病理生理状态。两个肿瘤抑制基因家族合作的能力 在细胞功能中提供了一个令人兴奋的和重要的新的研究成果， 癌症的发展。这一点最近得到了国会的认可，国会要求国家癌症研究所 研究脑硬化综合症（TSC），一种遗传性疾病， 肿瘤生长在身体的多个器官，包括脑，心脏，肾，肺， 肝脏眼睛或皮肤因为它与癌细胞的失控生长有相似之处。 许多科学家认为，确定TSC中肿瘤生长的原因可以开辟道路 癌症的治疗方法。委员会鼓励NCI支持方案 研究TSC的分子和细胞基础，以及TSC在肿瘤发展中的作用。 它与TGF-β通路相互作用的能力是理解这一过程的新环节。

In hematopoiesis, the need to continuously generate large numbers of maturing cells of eight distinct lineages from small numbers of stem cells requires a highly complex series of events. Hematopoietic stem cells (HSC), which can remain quiescent for months, must retain the abilities to differentiate into all lineages, to self-renew and to long-term repopulation marrow (LTRA). Numerous critical interactions controlling hematopoiesis are regulated by soluble or extracellular mediators which can have overlapping, additive and/or opposing functions on a given cell type. Transforming growth factor beta-1 (TGF-b1) is one of these critical regulators of hematopoiesis since our in vitro and in vivo work indicates that TGF-b is a regulator of all stages of hematopoiesis. A current priority is to further define the physiological relevance of TGF-b and determine the mechanisms by which it exerts its varied and complex effects. Important questions remain to be answered. Are the pleiotropic effects of TGF-b on hematopoiesis caused by distinct roles for intracellular mediators, Smad2 and Smad3, or crosstalk with other signal transduction pathways? What are the relative contributions of autocrine and paracrine TGF-b in HSC regulation? Can alteration of intracellular TGF-b signals alter differentiation outcomes? We have found that TGF-b1 regulates both HSC quiesence and survival through autocrine and paracrine mechanisms. Furthermore, neutralization of autocrine TGF-b in HSC causes a more rapid engraftment with fewer cells needed for bone marrow transplantation. In contrast, neutralization of autocrine TGF-b in human HSC in the presence of stem cell factor stimulates the production of erythroid progenitors in the absence of erythropoietin. Defining the mechanism(s) of autocrine TGF-b actions on regulating HSC will present new therapeutic opportunities. Furthermore, we have found that Smad2/3 are intracellular sensors that regulate commitment to myeloid differentiation in response to pharmacologic agents. All trans retinoic acid (ATRA) stimulates granulocytic differentiation by stimulating a phosphatase activity which dephosphorylates Smad2/3; while vitamin D3 stimulates monocytic differentiation through phosphorylation of Smad2/3. In addition, crosstalk between different members of the MAPK signaling pathways and the Smad pathway alters the outcomes of myeloid and erythroid differentiation. In addition, we have shown that Smad2 and Smad3 have different effects on early hematopoietic function. Thus, attenuation of specific signals has profound effects on hematopoietic outcomes. Since alterations in TGF-b, its receptors and downstream effectors (SMADs) have all been implicated in tumorigenesis, these studies could provide insights into malignant processes. TGF-b1 inhibits proliferation by restricting passage through the G1 phase of the cell cycle, in part through rapid transcriptional activation of genes such as cell cycle inhibitors. We recently found the tuberlin sclerosis gene product 2, another tumor suppressor gene that causes growth arrest in G1, directly interacts with Smad2 an transcriptional activation mediated by TGF-b (manuscript in press). Moreover, we have shown that tuberin is a powerful stimulator of TGF-b1-regulated transcription and differentiation events in the myeloid cells. Thus, the losses of functional tuberin and/or Smads can result in uncontrolled cell proliferation with a block in differentiation. Thus, subtle yet chronic changes in TGF-b1 regulation can lead to pathophysiological states. This ability of two tumor suppressor gene families to collaborate in cellular functions provides an exciting and important new avdenue of study pertaining to the development of cancers. This was recently recognized by congress in that it asked the NCI to study Tuberous sclerosis complex (TSC),a genetic disorder that triggers uncontrollable tumor growth in multiple organs of the body, including the brain, heart, kidneys, lungs, liver, eyes or skin. In light of its similarities to the uncontrolled growth of cancer cells. Many scientists believe that determining the cause of tumor growth in TSC could open the way for cures and treatments for cancer as well. The Committee encourages NCI to support programs examining the molecular and cellular basis of TSC, and the role of TSC in tumor development. Its ability to interact with TGF-beta pathway is an new link in understanding this process.