The Bcr-Abl tyrosine kinase activates mitogenic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells

Chen, David; Reuther, Gary W.; Pendergast, Ann Marie

doi:10.1038/sj.onc.1201400

Cited by 196 publications

(146 citation statements)

References 35 publications

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“…In combination with previous studies which showed that BCR ± ABL expression led to proliferation of factor-dependent murine hematopoietic cell lines (Daley and Baltimore, 1988;Hariharan et al, 1988;Laneuville et al, 1991), these data suggested that BCR ± ABL activated mitogenic as well as di erentiative pathways. In a recent study, Cortez et al, (1997) demonstrated that expression of BCR ± ABL in growth arrested 32D cells stimulated cells to reenter the cell cycle. This was associated with activation of RAS/MAP kinase pathways (both Erk and JNK), D-type cyclins and cdk2.…”

Section: Discussionmentioning

confidence: 99%

“…This was associated with activation of RAS/MAP kinase pathways (both Erk and JNK), D-type cyclins and cdk2. In fact, previous studies had also identi®ed genes downstream of BCR ± ABL such as RAS (Cortez et al, 1995(Cortez et al, , 1996Tauchi and Broxmeyer, 1995;Elefanty et al, 1997), cyclin D1 (Afar et al, 1995) and c-MYC (Cleveland et al, 1989;Sawyers et al, 1992;Afar et al, 1994) which were very likely to play a role in proliferation. Recent evidence has linked RAS signalling to cyclin D1/cdk4 activation (Albanese et al, 1995;Aktas et al, 1997;Peeper et al, 1997) and it has been shown that induction of S phase in REF52 cells requires co-expression of both RAS and c-MYC (Leone et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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Expression of BCR – ABL in M1 myeloid leukemia cells induces differentiation without arresting proliferation

et al. 1999

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The mechanism leading to the expanding population of maturing myeloid cells which characterises chronic myeloid leukemia (CML) remains obscure. Because of its ability to mimic the proliferative and cell survival functions of hematopoietic growth factors, we hypothesized that the oncogene activated in CML, BCR ± ABL, might also in¯uence di erentiation. To test this hypothesis, we examined the e ects of expressing BCR ± ABL on the myeloid di erentiation of murine M1 leukemic cells, which cease dividing and di erentiate into macrophages in the presence of the cytokines leukemia inhibitory factor (LIF) or interleukin (IL)-6. We found that BCR ± ABL induced macrophage di erentiation in M1 cells, accompanied by increased expression of macrophage cell surface markers and the acquisition of phagocytic ability. Interestingly, clones of M1 cells which expressed BCR ± ABL remained in cell cycle and were refractory to the growth inhibition and apoptosis induced by IL-6 or LIF in parental M1 cells. These cells also expressed inappropriately high levels of c-MYC mRNA for their degree of di erentiation, which may have been important in maintaining cellular proliferation. These data suggest that BCR ± ABL can stimulate both di erentiation and proliferation and that these characterisitics may contribute to the phenotype observed in CML.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression of BCR – ABL in M1 myeloid leukemia cells induces differentiation without arresting proliferation

et al. 1999

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“…22 Thus, Bcr-Abl inhibits apoptosis and induces G1/S transition. [24][25][26][27] Bcr-Abl blocks caspases and activates CDKs by several mechanisms (Figure 1). Bcr-Abl induces HSP70, which blocks apoptosis.…”

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confidence: 99%

Do cells need CDK2 and...Bcr-Abl?

Blagosklonny

2003

Cell Death Differ

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“…This leads to the constitutive activation of the focal adhesion kinase (FAK) (Gotoh et al, 1995), redistribution of ®lamentous (F) actin (McWhirter and Wang, 1993), and an increase in the level of spontaneous motility (Salgia et al, 1995). Perturbation of cell cycle regulation is considered an early event in P210 and P190Bcr-abl oncogenesis (Cortez et al, 1997). Inducible expression of both oncoproteins results in the activation of the cell cycle machinary, enhanced DNA synthesis, and the augmentation of mitogenic signals (Cortez et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Perturbation of cell cycle regulation is considered an early event in P210 and P190Bcr-abl oncogenesis (Cortez et al, 1997). Inducible expression of both oncoproteins results in the activation of the cell cycle machinary, enhanced DNA synthesis, and the augmentation of mitogenic signals (Cortez et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Early events in leukemogenesis in P190Bcr-abl transgenic mice

et al. 2000

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The activated tyrosine kinase, Bcr-abl, is implicated in a number of hematopoietic malignancies. The exact biological mechanism by which the kinases transforms cells is still not well delineated. Previous data has suggested that the inhibition of apoptosis and the deregulation of cell cycle progression as the result of P210Bcr-abl expression might contribute to leukemogenesis. In vitro systems in which Bcr-Abl is over-expressed have concluded that similar growth regulatory pathways are a ected as a result of the expression of both P210 and P190Bcr-abl. Here, we utilized an in vitro P190Bcr-abl leukemia mouse model to dissect the early events that contribute to transformation by this isoform of Bcr-Abl. In this mouse model P190Bcr-abl is expressed as a low but physiologically relevant level in that all mice develop pre-B leukemia lymphomas. We show that cell cycle and apoptotic responses to DNA damage are intact in bone marrow and spleen cells of such animals. We also demonstrate a normal induction of p21 WAF-1/CIP1 in both hematopoietic and non-hematopoietic tissue as a result of genotoxic stress. We suggest that P190Bcr-abl induced transformation is di erent than that of P210Bcr-abl.

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The Bcr-Abl tyrosine kinase activates mitogenic signaling pathways and stimulates G1-to-S phase transition in hematopoietic cells

Cited by 196 publications

References 35 publications

Expression of BCR – ABL in M1 myeloid leukemia cells induces differentiation without arresting proliferation

Expression of BCR – ABL in M1 myeloid leukemia cells induces differentiation without arresting proliferation

Do cells need CDK2 and...Bcr-Abl?

Early events in leukemogenesis in P190Bcr-abl transgenic mice

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