P62dok, a Negative Regulator of Ras and Mitogen-Activated Protein Kinase (Mapk) Activity, Opposes Leukemogenesis by P210bcr-abl
نویسندگان
چکیده
p62(dok) has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210(bcr-abl) oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62(dok) in normal cell signaling as well as in p210(bcr-abl) leukemogenesis are as yet not fully understood. Here we show, in hemopoietic and nonhemopoietic cells derived from p62(dok)-(/)- mice, that the loss of p62(dok) results in increased cell proliferation upon growth factor treatment. Moreover, Ras and mitogen-activated protein kinase (MAPK) activation is markedly sustained in p62(dok)-(/)- cells after the removal of growth factor. However, p62(dok) inactivation does not affect DNA damage and growth factor deprivation-induced apoptosis. Furthermore, p62(dok) inactivation causes a significant shortening in the latency of the fatal myeloproliferative disease induced by retroviral-mediated transduction of p210(bcr-abl) in bone marrow cells. These data indicate that p62(dok) acts as a negative regulator of growth factor-induced cell proliferation, at least in part through downregulating Ras/MAPK signaling pathway, and that p62(dok) can oppose leukemogenesis by p210(bcr-abl).
منابع مشابه
Negative Regulator of Ras and Mitogen - activated Protein Kinase ( MAPK ) Activity , Opposes Leukemogenesis by p 210 bcr - abl Antonio
p62 dok has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210 bcr-abl oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62 dok in normal cell signaling as well as in p210 bcr-abl leukemogenesis are as yet not fully understood....
متن کاملp 62 dok , a Negative Regulator of Ras and Mitogen - activated Protein Kinase ( MAPK ) Activity , Opposes Leukemogenesis by p 210 bcr - abl Antonio
p62 dok has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210 bcr-abl oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62 dok in normal cell signaling as well as in p210 bcr-abl leukemogenesis are as yet not fully understood....
متن کاملPhosphoinositide 3-Kinase–Dependent Membrane Recruitment of P62dok Is Essential for Its Negative Effect on Mitogen-Activated Protein (Map) Kinase Activation
A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate cell proliferation is via the receptor tyrosine kinase/Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The output of this pathway is subjected to tight regulation of both positive and negative regulators. One such regulator is p62(dok), the prototype of a newly identified family of ad...
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متن کاملTyrosine phosphorylation of p62dok by p210bcr-abl inhibits RasGAP activity.
The t(9;22) chromosomal translocation is found in almost all patients with chronic myelogenous leukemia. The resultant Bcr-Abl fusion gene expresses a chimeric fusion protein p210(bcr-abl) with increased tyrosine kinase activity. Hematopoietic progenitors isolated from chronic myelogenous leukemia patients in the chronic phase contain constitutively tyrosine-phosphorylated p62(dok) protein. p62...
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ورودعنوان ژورنال:
- The Journal of Experimental Medicine
دوره 194 شماره
صفحات -
تاریخ انتشار 2001