Differential expression of Csk homologous kinase (CHK) in normal brain and brain tumors

Kim, Sun-Ok; Avraham, Shalom; Jiang, Shuxian; Zagożdżon, Radosław; Fu, Yue; Avraham, Hava

doi:10.1002/cncr.20442

Cited by 26 publications

(22 citation statements)

References 59 publications

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“…Nuclear localization of ectopic CHK has previously been observed in monkey kidney fibroblast COS-1 cells, and overexpression of CHK induced multinucleation, which in combination with other data, suggested a potential role of CHK in chromosome dynamics (Yamaguchi et al, 2001). Nuclear staining of endogenous CHK has also been reported in normal human brain tissues (Kim et al, 2004). It appears that nuclear CHK induces nuclear multilobulation in late S-phase and inhibition of proliferation (Nakayama and Yamaguchi, 2005).…”

Section: Chk Inhibits Src In Normal Colon Cellsmentioning

confidence: 88%

Decreased CHK protein levels are associated with Src activation in colon cancer cells

et al. 2007

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Src activation has been associated with colon cancers but the mechanism underlying Src activation is largely unknown. Csk-homologous kinase (CHK) can inhibit the kinase activity of certain Src kinase family members in vitro by phosphorylating the C-terminal tyrosine and by a non-catalytic mechanism. CHK was previously reported to be expressed primarily in brain and hematopoietic cells. We report herein that CHK is also expressed in normal colon cell lines. Furthermore, CHK protein levels are significantly decreased in various colon cancer cell lines and the decrease correlates with the increased specific activity of Src in these cell lines, while the level of the other Src inhibitory kinase, C-terminal Src kinase, is not significantly changed. CHK is also expressed in normal colon tissues but its expression level is decreased in colon cancer tissues collected from the same patients. Immunofluorescence microscopy shows that CHK colocalizes with Src in normal colon FHC cells. Overexpression of CHK in colon cancer cells results in inactivation of Src without phosphorylating Y530 at its C-terminus. In addition, CHK suppresses anchorage-independent cell growth and cell invasion of colon cancer cells. These results reveal a potentially important role for CHK in Src activation and tumorigenicity in colon cancer cells.

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Section: Chk Inhibits Src In Normal Colon Cellsmentioning

confidence: 88%

Decreased CHK protein levels are associated with Src activation in colon cancer cells

et al. 2007

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“…CHK is highly expressed in neural tissue, especially in neurons. It was shown that Csk and CHK exhibit opposite temporal expression in the CNS (12,13). Previously, we observed a different pattern of expression for CHK and Csk in brain malignancies (13).…”

Section: Introductionmentioning

confidence: 66%

“…It was shown that Csk and CHK exhibit opposite temporal expression in the CNS (12,13). Previously, we observed a different pattern of expression for CHK and Csk in brain malignancies (13). While Csk expression is not altered in brain malignancies, CHK expression is significantly downregulated in some brain tumor types (13).…”

Section: Introductionmentioning

confidence: 67%

“…Although CHK was primarily reported to act like Csk kinase and to inhibit activation of Src-family kinases, we showed that CHK, unlike Csk, participates in signaling mediated by the TrkA receptors (14). Accordingly, recent studies suggest CHK's involvement in neuronal differentiation (12,13,15). Importantly, our recent data suggest that CHK could serve as a natural suppressor of CXCR4 expression (16).…”

Section: Introductionmentioning

confidence: 75%

“…Previously, we observed a different pattern of expression for CHK and Csk in brain malignancies (13). While Csk expression is not altered in brain malignancies, CHK expression is significantly downregulated in some brain tumor types (13). The exact role of CHK in the nervous system has not been well elucidated.…”

Section: Introductionmentioning

confidence: 92%

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Csk homologous kinase inhibits CXCL12-CXCR4 signaling in neuroblastoma

Zagożdżon

Fu²,

Avraham³

2008

Int J Oncol

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Abstract. Neuroblastoma is the second most common pediatric malignancy. The clinical course of this disease ranges from spontaneous regression and good survival to highly malignant therapy-resistant tumors. There is a continuous need for genetic and biologic markers for the diverse clinical phenotypes observed in neuroblastoma patients. One of the known markers in neuroblastoma is expression of the CXCR4 chemokine receptor. CXCR4 expression correlates with high-stage disease, and the autocrine stimulation of CXCR4 by its ligand (CXCL12) was shown to be necessary for the survival of some neuroblastoma cells in vitro. However, the mechanisms responsible for activation of the CXCL12-CXCR4 autocrine pathway in neuroblastoma remain uncertain. Our previous findings suggest that Csk homologous kinase (CHK) is a physiological inhibitor of CXCR4 expression. Since CHK is highly expressed in neurons, we evaluated changes in CHK expression in human neuroblastoma. CHK protein expression was below detectable levels based on Western blot analyses in 13 out of 16 human neuroblastoma cell lines and in 6 out of 16 primary neuroblastoma tissues. When CHK expression was restored in IMR32 neuroblastoma cells by retrovirusmediated cDNA transfer, diminished CXCR4 mRNA and protein levels were observed, as assessed by RT-PCR and flow cytometry analyses, respectively. Furthermore, exogenous expression of CHK markedly suppressed the mRNA levels and secretion of the CXCL12 chemokine from IMR32 cells as well as inhibited the growth rate of these cells. Taken together, our data strongly suggest that CHK is capable of inhibiting the CXCL12-CXCR4 pathway in neuroblastoma.

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The immunoglobulin‐like cell adhesion molecule hepaCAM induces differentiation of human glioblastoma U373‐MG cells

Lee

Moh

Zhang

et al. 2009

J of Cellular Biochemistry

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Subsequent to our identification of a novel immunoglobulin-like cell adhesion molecule hepaCAM, we showed that hepaCAM is frequently lost in diverse human cancers and is capable of modulating cell motility and growth when re-expressed. Very recently, a molecule identical to hepaCAM (designated as GlialCAM) was found highly expressed in glial cells of the brain. Here, we demonstrate that hepaCAM is capable of inducing differentiation of the human glioblastoma U373-MG cells. Expression of hepaCAM resulted in a significant increase in the astrocyte differentiation marker glial fibrillary acid protein (GFAP), indicating that hepaCAM promotes glioblastoma cells to undergo differentiation. To determine the relationship between hepaCAM expression level and cell differentiation, we established two U373-MG cell lines expressing hepaCAM at different levels. The results revealed that high-level hepaCAM triggered a clear increase in GFAP expression as well as morphological changes characteristic of glioblastoma cell differentiation. Furthermore, high expression of hepaCAM significantly accelerated cell adhesion but inhibited cell proliferation and migration. Concomitantly, deregulation of cell cycle regulatory proteins was detected. Expectedly, the differentiation was noticeably less apparent in cells expressing low-level hepaCAM. Taken together, our findings suggest that hepaCAM induces differentiation of the glioblastoma U373-MG cells. The degree of cell differentiation is dependent on the expression level of hepaCAM.

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Differential expression of Csk homologous kinase (CHK) in normal brain and brain tumors

Cited by 26 publications

References 59 publications

Decreased CHK protein levels are associated with Src activation in colon cancer cells

Decreased CHK protein levels are associated with Src activation in colon cancer cells

Csk homologous kinase inhibits CXCL12-CXCR4 signaling in neuroblastoma

The immunoglobulin‐like cell adhesion molecule hepaCAM induces differentiation of human glioblastoma U373‐MG cells

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