Repression of c-Cbl leads to enhanced G-CSF Jak-STAT signaling without increased cell proliferation

Wang, Lin; Rudert, William A.; Loutaev, Inna; Roginskaya, Vera; Corey, Seth J.

doi:10.1038/sj.onc.1205670

Cited by 39 publications

(59 citation statements)

References 54 publications

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“…At higher levels of caspase activity, the ability of fragment N to counteract apoptosis is suppressed when it is cleaved at position 157. This latter cleavage event generates two fragments, N1 and N2, that in contrast to fragment N potently sensitizes HeLa cells toward cisplatin-induced apoptosis (Yang and Widmann, 2001). In the present study we show that a cell permeable peptide derived from the N2 fragment of RasGAP specifically sensitizes cancer cells to three different genotoxins commonly used in chemotherapy.…”

Section: Introductionmentioning

confidence: 65%

“…We have recently shown that fragment N2 potently sensitized the ability of cisplatin to kill the HeLa tumor cell line (Yang and Widmann, 2001). To assess whether fragment N2 could potentiate the apoptotic response induced by other genotoxins, HeLa cells, expressing or not fragment N2, were subjected to increasing concentrations of adriamycin and mitoxantrone (and cisplatin as control).…”

Section: Rasgap Fragment N2 Potentiates the Apoptotic Response Inducementioning

confidence: 99%

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A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells

Michod

Yang

Chen³

et al. 2004

Oncogene

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Treatment of many cancers relies on the combined action of several genotoxins, but the detrimental effect of these drugs on normal cells can cause severe side effects. One major challenge in anticancer therapy is therefore to increase the selectivity of current treatments toward cancer cells in order to spare normal cells. We have recently demonstrated that a RasGAP caspase cleavage fragment is able to sensitize HeLa cells towards cisplatininduced apoptosis. Here, we extend this observation by showing that this fragment also enhances cell death induced by adriamycin and mitoxantrone, two other widely used genotoxins. Furthermore, we have delineated a short sequence within this fragment that still bears the genotoxin-sensitization property. The peptide encoded by this sequence, when fused to the TAT cell permeation sequence, potently sensitized a number of tumors cells, but not normal cells, towards apoptosis induced by cisplatin, adriamycin and mitoxantrone. This sensitization effect was not mediated through modulation of NFjB activity or activation of the JNK and p38 MAPK pathways. Our results demonstrate the feasibility in enhancing the efficacy of currently used drugs to selectively kill cancer cells using peptides derived from pro-apoptotic caspase substrate fragments.

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Section: Introductionmentioning

confidence: 65%

Section: Rasgap Fragment N2 Potentiates the Apoptotic Response Inducementioning

confidence: 99%

A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells

Michod

Yang

Chen³

et al. 2004

Oncogene

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“…Signaling by activated caspases in the absence of an apoptotic response has been reported previously (Jaattela et al, 1998;De Maria et al, 1999;Yang and Widmann, 2001). Ras : GAP has been identified as a caspase 3 or caspase 3-like substrate that can be selectively cleaved to generate an anti-apoptotic signal in Jurkat cells (Yang and Widmann, 2001).…”

Section: Discussionmentioning

confidence: 96%

“…Ras : GAP has been identified as a caspase 3 or caspase 3-like substrate that can be selectively cleaved to generate an anti-apoptotic signal in Jurkat cells (Yang and Widmann, 2001). This selective cleavage is thought to act as a sensor to translate the extent of caspase 3 or caspase 3-like signaling since low levels of caspase 3 signaling generate the protective fragment of Ras : GAP while higher levels destroy this protective fragment (Yang and Widmann, 2001). We were unable to detect any cleavage of Ras : GAP in either parental or Raf expressing 23A2 myoblasts.…”

Section: Discussionmentioning

confidence: 99%

“…In (e), myoblasts were switched to DM with or without PD098059 for 6 h prior measuring cytosolic nucleosomes as described for Figure 4. Shown in each are the average of duplicates from one experiment, which are representative of two independent experiments apoptosis downstream of caspase 3 activation and the subsequent cleavage of caspase 3 substrates like PARP (Jaattela et al, 1998;Yang and Widmann, 2001). We, therefore, examined the A2 : Raf : CAAX clones for altered levels of Hsp70 or Ras : GAP.…”

Section: Effect Of Mek Inhibition On Raf Signalingmentioning

confidence: 99%

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Raf-induced effects on the differentiation and apoptosis of skeletal myoblasts are determined by the level of Raf signaling: abrogation of apoptosis by Raf is downstream of caspase 3 activation

2002

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We examined the effect of a constitutively active Raf protein (Raf-CAAX) on the differentiation and the coincident apoptosis of skeletal myoblasts. We found that a low level of Raf signaling leads to accelerated differentiation when compared to parental myoblasts, while a higher level of Raf signaling induces a transformed morphology and abrogates both differentiation and the coincident apoptosis. Raf signaling abrogates apoptosis without blocking the activation of caspase 3 and the subsequent cleavage of caspase 3 substrates. Eliminating the signal from Raf through MEK does not restore the ability to differentiate or to undergo apoptosis in the myoblasts with a high level of Raf signal, nor does it abrogate the accelerated differentiation observed in myoblasts with lower levels of Raf signal. Constitutive signaling through MEK is required, however, to maintain a transformed morphology. These results indicate that the effect of Raf on the differentiation and apoptosis of skeletal myoblasts is dictated by the level of Raf signaling, and that Raf signaling sufficient to abrogate the apoptosis coincident with differentiation does so downstream of caspase 3 signaling.

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The Cbl family proteins: Ring leaders in regulation of cell signaling

Swaminathan

Tsygankov

2006

Journal Cellular Physiology

278

349

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The proto-oncogenic protein c-Cbl was discovered as the cellular form of v-Cbl, a retroviral transforming protein. This was followed over the years by important discoveries, which identified c-Cbl and other Cbl-family proteins as key players in several signaling pathways. c-Cbl has donned the role of a multivalent adaptor protein, capable of interacting with a plethora of proteins, and has been shown to positively influence certain biological processes. The identity of c-Cbl as an E3 ubiquitin ligase unveiled the existence of an important negative regulatory pathway involved in maintaining homeostasis in protein tyrosine kinase (PTK) signaling. Recent years have also seen the emergence of novel regulators of Cbl, which have provided further insights into the complexity of Cbl-influenced pathways. This review will endeavor to provide a summary of current studies focused on the effects of Cbl proteins on various biological processes and the mechanism of these effects. The major sections of the review are as follows: Structure and genomic organization of Cbl proteins; Phosphorylation of Cbl; Interactions of Cbl; Localization of Cbl; Mechanism of effects of Cbl: (a) Ubiquitylation-dependent events: This section elucidates the mechanism of Cbl-mediated downregulation of EGFR and details the PTK and non-PTKs targeted by Cbl. In addition, it addresses the functional requirements for E3 Ubiquitin ligase activity of Cbl and negative regulation of Cbl-mediated downregulation of PTKs, (b) Adaptor functions: This section discusses the mechanisms of adaptor functions of Cbl in mitogen-activated protein kinase (MAPK) activation, insulin signaling, regulation of Ras-related protein 1 (Rap1), PI-3 0 kinase signaling, and regulation of Rho-family GTPases and cytoskeleton; Biological functions: This section gives an account of the diverse biological functions of Cbl and includes the role of Cbl in transformation, T-cell signaling and thymus development, B-cell signaling, mast-cell degranulation, macrophage functions, bone development, neurite growth, platelet activation, muscle degeneration, and bacterial invasion; Conclusions and perspectives.

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Repression of c-Cbl leads to enhanced G-CSF Jak-STAT signaling without increased cell proliferation

Cited by 39 publications

References 54 publications

A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells

A RasGAP-derived cell permeable peptide potently enhances genotoxin-induced cytotoxicity in tumor cells

Raf-induced effects on the differentiation and apoptosis of skeletal myoblasts are determined by the level of Raf signaling: abrogation of apoptosis by Raf is downstream of caspase 3 activation

The Cbl family proteins: Ring leaders in regulation of cell signaling

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