BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl

Hemmeryckx, Bianca; Reichert, Anja; Watanabe, Meguru; Kaartinen, Vesa; Jong, Ron de; Pattengale, Paul K.; Groffen, John; Heisterkamp, Nora

doi:10.1038/sj.onc.1205452

Cited by 31 publications

(33 citation statements)

References 37 publications

(28 reference statements)

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“…The authors of this paper did not examine the levels of CrkL (Imaizumi et al, 1999). Furthermore, in CrkL knockout study, it is described that the expression level of CrkII was not altered in the mice lacking CrkL (Hemmeryckx et al, 2002). In fact, we have established CrkII knockdown cells by using three human sarcoma cell lines and a glioblastoma cell line, and we did not observe the increase of the levels of CrkL in these cell lines (data not shown).…”

Section: Discussionmentioning

confidence: 72%

Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS

et al. 2006

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Signaling adaptor protein Crk regulates cell motility and growth through its targets Dock180 and C3G, those are the guanine-nucleotide exchange factors (GEFs) for small GTPases Rac and Rap, respectively. Recently, overexpression of Crk has been reported in various human cancers. To define the role for Crk in human cancer cells, Crk expression was targeted in the human ovarian cancer cell line MCAS through RNA interference, resulting in the establishment of three Crk knockdown cell lines. These cell lines exhibited disorganized actin fibers, reduced number of focal adhesions, and abolishment of lamellipodia formation. Decreased Rac activity was demonstrated by pull-down assay and FRET-based timelapse microscopy, in association with suppression of both motility and invasion by phagokinetic track assay and transwell assay in these cells. Furthermore, Crk knockdown cells exhibited slow growth rates in culture and suppressed anchorage-dependent growth in soft agar. Tumor forming potential in nude mice was attenuated, and intraperitoneal dissemination was not observed when Crk knockdown cells were injected into the peritoneal cavity. These results suggest that the Crk is a key component of focal adhesion and involved in cell growth, invasion, and dissemination of human ovarian cancer cell line MCAS.

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Section: Discussionmentioning

confidence: 72%

Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS

et al. 2006

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“…However, a recent study demonstrated that CML can still develop in CrkLknockout mice when bred to BCR-ABL P190-transgenic mice [52]. Although the lack of phenotype may be explained by mouse strain-specific effects or functional compensation by other related proteins, these results do suggest that CrkL is not absolutely required for leukemogenesis in vivo.…”

Section: Discussionmentioning

confidence: 93%

T cell development and function in CrkL‐deficient mice

et al. 2003

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The adapter protein CrkL has been implicated in multiple signal transduction pathways in hematopoietic cells. In T lymphocytes, the recruitment of CrkL-C3G complexes has been correlated with hyporesponsiveness, implicating CrkL as a potential negative regulator. To test this hypothesis we examined T cell activation in CrkL-deficient mice. The CrkL -/-genotype was partially embryonic lethal. In viable CrkL -/-mice, peripheral blood counts were normal. The thymus from CrkL -/-mice had 40% fewer cells compared to littermates, but the proportion of thymocyte subsets was comparable. There was no discernable alteration in T cell function as reflected by T cell numbers, expression of memory markers, IL-2 production, proliferation, and differentiation into Th1/Th2 phenotypes. Immunization induced comparable levels of IgG2a and IgG1 antibodies. Chimeric mice, generated by transfer of CrkL -/-fetal liver cells into irradiated RAG2-/-recipients, also showed normal T cell function, arguing against selection via partial embryonic lethality. Our results indicate that CrkL is not absolutely required for T cell development or function, and argue against it being an essential component of a negative regulatory pathway in TCR signaling.

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“…The inhibition of complexes mediated by the CRKLSH3(1) domain in CML cell lines and primary isolates from patient cells can inhibit the proliferation of these cells . By contrast, enhanced expression of CRKL has just the opposite e ect: mice transgenic for the p190 Bcr ± Abl protein developed leukaemia more rapidly when CRKL was overexpressed four-to sixfold (Hemmeryckx et al, 2001). …”

Section: Human Leukaemic Abl Kinasesmentioning

confidence: 99%