A MAPK-positive Feedback Mechanism for BLR1 Signaling Propels Retinoic Acid-triggered Differentiation and Cell Cycle Arrest

Wang, Jianrong; Yen, Andrew

doi:10.1074/jbc.m708471200

Cited by 48 publications

(113 citation statements)

References 33 publications

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“…This study is the first to indicate the importance of the TKB domain of c-Cbl in RAinduced HL-60 cell differentiation and cell cycle arrest. We have previously shown that Raf-driven MAPK signaling propels RA-induced differentiation (39). In contrast to WT c-Cbl or its C381A Ring mutant, the G306E mutant failed to drive RAF/ERK MAPK activation, which is needed to promote cell differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…The results from the Western blots of pERK were consistent with the flow cytometric measurements. We previously reported that RA caused a Raf activation necessary to induce differentiation and G 0 arrest (39). To investigate how the G306E mutant affected RAF, phosphorylation of RAF (Ser 621 ) was compared among different cell lines.…”

Section: C-cbl Tkb Mutant G306e Failed To Enhance Cd11b Expression Anmentioning

confidence: 99%

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c-Cbl Tyrosine Kinase-binding Domain Mutant G306E Abolishes the Interaction of c-Cbl with CD38 and Fails to Promote Retinoic Acid-induced Cell Differentiation and G0 Arrest

Shen

Yen

2009

Journal of Biological Chemistry

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Retinoic acid (RA) causes HL-60 human myeloblastic leukemia cell myeloid differentiation that is dependent on MAPK signaling. The process is propelled by c-Cbl, which binds the CD38 receptor as part of a signaling complex generating MAPK signaling. Here we report that the capability of c-Cbl to do this is lost in the G306E tyrosine kinase-binding domain mutant. Retinoic acid (RA), 2 a form of vitamin A, can cause activation of MAPK signaling leading to induced cell differentiation and G 0 cell cycle arrest (1-2). Because of this, RA has been used therapeutically for the chemoprevention and treatment of cancer (3), notably acute promyelocytic leukemia, making its mechanism of action of significant interest. The HL-60 human myeloblastic leukemia cell line serves as a model for studying differentiation induction therapy and the mechanism of RA action (4 -6). The HL-60 cell line was established from peripheral blood leukocytes of a patient originally diagnosed with acute promyelocytic leukemia (4), which was retrospectively re-evaluated to be acute myeloblastic leukemia (7). HL-60 cells undergo G 0 cell cycle arrest and myeloid differentiation in response to RA or monocytic differentiation in response to 1,25-dihydroxyvitamin D 3 . Induced differentiation depends on hyperactive MAPK signaling (1, 8). c-Cbl contributes propulsion to this process (9, 10). It is part of a signaling complex connected to the CD38 receptor that activates the RAF/MEK/ ERK MAPK signaling axis to drive differentiation and G 0 cell cycle arrest (9).The 120-kDa product of the c-Cbl protooncogene is a prominent component of tyrosine kinase signaling cascades downstream of activated cell surface receptors, including the epidermal growth factor receptor, the B cell receptor, Fc receptor, and cytokine receptors (11,12). Cbl proteins have a highly conserved N-terminal domain termed the tyrosine kinase-binding (TKB) domain, which binds to phosphotyrosines on activated receptor-tyrosine kinases and other signaling proteins (13, 14), a short linker region, and a Ring finger domain that binds to ubiquitin-conjugating enzymes (15, 16). The Ring finger domain of c-Cbl presents the most conserved region among Cbl family proteins, and it is implicated as an important element in the function of Cbl proteins (17)(18)(19). The TKB domain contains a four-helix bundle, EF-hand calcium-binding domain, and a variant SH2 domain that binds to phosphotyrosine residues (13,20). Several features of the Cbl/Zap-70 complex (13) suggest that the four-helix bundle, EF-hand, and SH2 domains together form an interactive structure that is crucial for phosphoprotein recognition. Studies by Thien et al. (21) indicated that the TKB mutation, G306E, fails to bind phosphotyrosine residues and is a loss of function mutation in the c-Cbl TKB domain.Cbl interacts with a number of intracellular signaling molecules including various receptors, adaptors, cytoskeletal proteins, ubiquitin, and structural proteins via its various domains (22,23). One of the receptors is CD38. The human c...

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Section: Discussionmentioning

confidence: 99%

Section: C-cbl Tkb Mutant G306e Failed To Enhance Cd11b Expression Anmentioning

confidence: 99%

c-Cbl Tyrosine Kinase-binding Domain Mutant G306E Abolishes the Interaction of c-Cbl with CD38 and Fails to Promote Retinoic Acid-induced Cell Differentiation and G0 Arrest

Shen

Yen

2009

Journal of Biological Chemistry

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“…1E), indicating that expressing or maintaining the constitutive Beclin 1 depends on the basal activity of MEK/ERK. However, knockdown of Raf1 by RNA interference or constitutive expression of the Raf1 CR3 domain, the active Raf1, which was proven functional previously (38), hardly affected the basal activity of MEK/ERK or the constitutive Beclin 1 (Fig. 1, E and F), suggesting that basal MEK/ERK activity conferring the constitutive Beclin 1 may largely be independent of Raf1.…”

Section: Expression Of Beclin 1 Is Mek/erk-dependent-mentioning

confidence: 98%

“…Immunoblotting and Co-immunoprecipitation-Western blotting and co-immunoprecipitation were performed as described previously (38).…”

Section: Methodsmentioning

confidence: 99%

A Non-canonical MEK/ERK Signaling Pathway Regulates Autophagy via Regulating Beclin 1

Wang

Whiteman

Lian

et al. 2009

Journal of Biological Chemistry

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291

259

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“…The fluorescence intensity represents the relative expression level of the marker in response to vitamin D3. Functional differentiation was measured by a NBT reduction assay as previously described (28). For cell growth arrest assay, the distribution of cells in the cell cycle was measured by flow cytometric analysis of hypotonic propidium iodide-stained nuclei to derive the percentage of cells with G 1/0 DNA content as previously described (28).…”

Section: Methodsmentioning

confidence: 99%

Vitamin D3 Induces Autophagy of Human Myeloid Leukemia Cells

Wang

Lian

Zhao

et al. 2008

Journal of Biological Chemistry

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119

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Vitamin D3 causes potent suppression of various cancer cells; however, significant supraphysiological concentrations of this compound are required for antineoplastic effects. Current combinatorial therapies with vitamin D3 are restricted to differentiation effects. It remains uncertain if autophagy is involved in vitamin D3 inhibition on leukemia cells. Here we show that besides triggering differentiation and inhibiting apoptosis, which was previously known, vitamin D3 triggers autophagic death in human myeloid leukemia cells. Inhibiting differentiation does not efficiently diminish vitamin D3 suppression on leukemia cells. Vitamin D3 up-regulates Beclin1, which binds to class III phosphatidylinositol 3-kinase to trigger autophagy. Vitamin D3 phosphorylates Bad in its BH3 domain, resulting in disassociation of the apoptotic Bad-Bcl-xL complex and association of Bcl-xL with Beclin1 and ultimate suppression of apoptotic signaling. Knockdown of Beclin1 eliminates vitamin D3-induced autophagy and inhibits differentiation but activates apoptosis, suggesting that Beclin1 is required for both autophagy and differentiation, and autophagy cooperates with differentiation but excludes apoptosis, in which Beclin1 acts as an interface for these three different cascades. Moreover, additional up-regulation of autophagy, but not apoptosis, dramatically improves vitamin D3 inhibition on leukemia cells. These findings extend our understanding of the action of vitamin D3 in antineoplastic effects and the role of Beclin1 in regulating multiple cellular cascades and suggest a potentially promising strategy with a significantly better antileukemia effect.1,25-Dihydroxyvitamin D3, the hormonally active form of vitamin D3, plays critical roles in regulating cellular and physiological responses. Treatment of vitamin D3 potently inhibits cell proliferation in a wide range of cancer cells, including myeloid leukemia and carcinomas of the breast, prostate, colon, skin, and brain and inhibits angiogenesis, tumor invasion, and metastases (1-8), suggesting that vitamin D3 has potential applications in cancer prevention and treatment. Vitamin D3 is known to inhibit cancer cell proliferation through the induction of differentiation, which is dependent on the signaling mechanisms involving down-regulation of Akt and its disassociation with Raf1 and subsequent activation of Raf/MEK/ERK 2

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A MAPK-positive Feedback Mechanism for BLR1 Signaling Propels Retinoic Acid-triggered Differentiation and Cell Cycle Arrest

Cited by 48 publications

References 33 publications

c-Cbl Tyrosine Kinase-binding Domain Mutant G306E Abolishes the Interaction of c-Cbl with CD38 and Fails to Promote Retinoic Acid-induced Cell Differentiation and G0 Arrest

c-Cbl Tyrosine Kinase-binding Domain Mutant G306E Abolishes the Interaction of c-Cbl with CD38 and Fails to Promote Retinoic Acid-induced Cell Differentiation and G0 Arrest

A Non-canonical MEK/ERK Signaling Pathway Regulates Autophagy via Regulating Beclin 1

Vitamin D3 Induces Autophagy of Human Myeloid Leukemia Cells

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