Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Embryonal central nervous system (CNS) tumors, which comprise medulloblastoma, are the most common malignant brain tumors in children. The role of the growth factor scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-Met in these tumors has been until now completely unknown. In the present study, we show that human embryonal CNS tumor cell lines and surgical tumor specimens express SF/HGF and c-Met. Furthermore, c-Met mRNA expression levels statistically significantly correlate with poor clinical outcome. Treatment of medulloblastoma cells with SF/HGF activates c-Met and downstream signal transduction as evidenced by c-Met, mitogen-activated protein kinase, and Akt phosphorylation. SF/HGF induces tumor cell proliferation, anchorage-independent growth, and cell cycle progression beyond the G1-S checkpoint. Using dominant-negative Cdk2 and a degradation stable p27 mutant, we show that cell cycle progression induced by SF/HGF requires Cdk2 function and p27 inhibition. SF/HGF also protects medulloblastoma cells against apoptosis induced by chemotherapy. This cytoprotective effect is associated with reduction of proapoptotic cleaved poly(ADP-ribose) polymerase and cleaved caspase-3 proteins and requires phosphoinositide 3-kinase activity. SF/HGF gene transfer to medulloblastoma cells strongly enhances the in vivo growth of s.c. and intracranial tumor xenografts. SF/HGF-overexpressing medulloblastoma xenografts exhibit increased invasion and morphologic changes that resemble human large cell anaplastic medulloblastoma. This first characterization establishes SF/HGF:c-Met as a new pathway of malignancy with multifunctional effects in human embryonal CNS tumors.
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PMID:The scatter factor/hepatocyte growth factor: c-met pathway in human embryonal central nervous system tumor malignancy. 1623 Mar 98

Signaling by the sonic hedgehog (Shh) pathway is essential for neural precursor population expansion during normal central nervous system (CNS) development, and is implicated in the childhood brain tumor, medulloblastoma. The proto-oncogene N-myc plays essential roles as a downstream effector of Shh proliferative effects in neural precursors of the cerebellum, where medulloblastomas arise. It is likely that N-Myc has analogous functions in medulloblastomas and other CNS tumors where it is highly expressed due to altered regulation or gene amplification. Myc destabilization occurs in response to phosphorylation by GSK-3beta. N-Myc degradation is required for cerebellar neural precursors to exit the cell cycle. During mitosis in cerebellar neural precursors, levels of N-Myc primed for phosphorylation by GSK-3beta increase, due to cdk1 complex activity towards N-Myc. GSK-3beta is kept in check by insulin-like growth factor signaling, which also plays critical roles in brain development and cancer. These findings indicate that therapeutic strategies targeting N-myc and the IGF pathway might be effective against medulloblastoma.
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PMID:Neural precursor cycling at sonic speed: N-Myc pedals, GSK-3 brakes. 1632 94