Objective: To survey the role of protein tyrosine kinases (PTKs) in the pathogenesis of several hematopoietic malignancies. Methods: By reviewing the published laboratory and clinical studies on PTK-related oncoprotei...Objective: To survey the role of protein tyrosine kinases (PTKs) in the pathogenesis of several hematopoietic malignancies. Methods: By reviewing the published laboratory and clinical studies on PTK-related oncoproteins and their causative role in some leukemias and lymphomas. Results: Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiations. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) plays an etiologic role in several clonal hematopoietic malignancies. For example, the PTK product of the BCR-ABL fusion gene resulting from the t (9; 22) translocation exhibits several fold higher tyrosine kinase activity than the product of the ABL gene. Evidence suggests that the BCR-ABL oncoprotein alone is sufficient to case chronic myelogenous leukemia (CML) and other Ph positive acute leukemia. PTK over-activity resulting from chromosomal translocations creating TEL-ABL, TEL-JAK2 and TEL-PDGFRβ fusion proteins plays an important role in the pathogenesis of other types of leukemia. Another example occurs in anaplastic large cell lymphoma (ALCL). Experimental and clinical evidences indicate that translocations involving ALK gene on chromosome 2p23, most commonly resulting in an NPM-ALK fusion oncogene, result in constitutive activation of ALK and cause ALCL. This group of lymphomas is now named ALK positive lymphoma or ALKoma. Conclusion: Genetic lesions creating aberrant fusion proteins that result in excessive PTK activity are increasingly being recognized as central to the pathogenesis of hemotopoietic malignancies. These chimeric PTK molecules represent attractive disease-specific targets against which new classes therapeutic agents are being developed.展开更多
The malignancy of a cancer is due partly to its poor differentiation. Genistein, a protein tyrosine kinase inhibitor, is found to induce the highly malignant B16-BL6 mouse melanoma cells to differentiate to mature phe...The malignancy of a cancer is due partly to its poor differentiation. Genistein, a protein tyrosine kinase inhibitor, is found to induce the highly malignant B16-BL6 mouse melanoma cells to differentiate to mature phenotypes. When Triton X-100 insoluble fraction of the differentiated cells is prepared and analyzed, tyrosine phosphorylation levels of three cytoskeleton-associated proteins (65, 60 and 53 ku respectively) are found to decrease dramatically. But no any change is found when phosphotyrosine contents of the cytosol fraction or the total cellular protein preparations are evaluated. It is concluded that cytoskeleton-associated protein tyrosine phosphorylation may be involved in the control of differentiation of cancer cells. The decrease of phosphotyrosine contents of cytoskeleton-associated proteins may be one of the important mechanisms underlying the differentiation induction of cancer cells by anticancer agents.展开更多
细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用,肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(prote in tyrosine k inases,PTKs)介导的信号转导途径,...细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用,肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(prote in tyrosine k inases,PTKs)介导的信号转导途径,分别介绍了受体酪氨酸激酶介导的Ras/Raf/MAPK和PI-3K/Akt途径,非受体酪氨酸激酶介导的Src、Bcr-Ab l和JAK/STAT途径。以此5条信号转导通路中参与的重要蛋白分子为靶点,统计和介绍了相关的已经上市或处于临床研究的抗肿瘤药物。展开更多
基金This work was partially supported by a grant from World Health Organization Fellowship (XS) (WPRO AWARD No. 0008/99).
文摘Objective: To survey the role of protein tyrosine kinases (PTKs) in the pathogenesis of several hematopoietic malignancies. Methods: By reviewing the published laboratory and clinical studies on PTK-related oncoproteins and their causative role in some leukemias and lymphomas. Results: Protein tyrosine kinases are key participants in signal transduction pathways that regulate cellular growth, activation and differentiations. Aberrant PTK activity resulting from gene mutation (often accompanying chromosome translocation) plays an etiologic role in several clonal hematopoietic malignancies. For example, the PTK product of the BCR-ABL fusion gene resulting from the t (9; 22) translocation exhibits several fold higher tyrosine kinase activity than the product of the ABL gene. Evidence suggests that the BCR-ABL oncoprotein alone is sufficient to case chronic myelogenous leukemia (CML) and other Ph positive acute leukemia. PTK over-activity resulting from chromosomal translocations creating TEL-ABL, TEL-JAK2 and TEL-PDGFRβ fusion proteins plays an important role in the pathogenesis of other types of leukemia. Another example occurs in anaplastic large cell lymphoma (ALCL). Experimental and clinical evidences indicate that translocations involving ALK gene on chromosome 2p23, most commonly resulting in an NPM-ALK fusion oncogene, result in constitutive activation of ALK and cause ALCL. This group of lymphomas is now named ALK positive lymphoma or ALKoma. Conclusion: Genetic lesions creating aberrant fusion proteins that result in excessive PTK activity are increasingly being recognized as central to the pathogenesis of hemotopoietic malignancies. These chimeric PTK molecules represent attractive disease-specific targets against which new classes therapeutic agents are being developed.
文摘The malignancy of a cancer is due partly to its poor differentiation. Genistein, a protein tyrosine kinase inhibitor, is found to induce the highly malignant B16-BL6 mouse melanoma cells to differentiate to mature phenotypes. When Triton X-100 insoluble fraction of the differentiated cells is prepared and analyzed, tyrosine phosphorylation levels of three cytoskeleton-associated proteins (65, 60 and 53 ku respectively) are found to decrease dramatically. But no any change is found when phosphotyrosine contents of the cytosol fraction or the total cellular protein preparations are evaluated. It is concluded that cytoskeleton-associated protein tyrosine phosphorylation may be involved in the control of differentiation of cancer cells. The decrease of phosphotyrosine contents of cytoskeleton-associated proteins may be one of the important mechanisms underlying the differentiation induction of cancer cells by anticancer agents.
文摘细胞信号转导(signal transduction)在细胞的代谢、分裂、分化、生物功能及死亡过程中起着重要作用,肿瘤的发生和发展与细胞信号转导过度激活有关。本文简要阐述了蛋白酪氨酸激酶(prote in tyrosine k inases,PTKs)介导的信号转导途径,分别介绍了受体酪氨酸激酶介导的Ras/Raf/MAPK和PI-3K/Akt途径,非受体酪氨酸激酶介导的Src、Bcr-Ab l和JAK/STAT途径。以此5条信号转导通路中参与的重要蛋白分子为靶点,统计和介绍了相关的已经上市或处于临床研究的抗肿瘤药物。
