Biological role of anaplastic lymphoma kinase in neuroblastoma.
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor originally identified as part of the chimeric nucleophosmin-ALK protein in the t(2;5) chromosomal rearrangement associated with anaplastic large cell lymphoma. We recently demonstrated that the ALK kinase is constitutively activated by gene amplification at the ALK locus in several neuroblastoma cell lines. Forming a stable complex with hyperphosphorylated ShcC, activated ALK modifies the responsiveness of the mitogen-activated protein kinase pathway to growth factors. In the present study, the biological role of activated ALK was examined by suppressing the expression of ALK kinase in neuroblastoma cell lines using an RNA interference technique. The suppression of activated ALK in neuroblastoma cells by RNA interference significantly reduced the phosphorylation of ShcC, mitogen-activated protein kinases, and Akt, inducing rapid apoptosis in the cells. By immunohistochemical analysis, the cytoplasmic expression of ALK was detected in most of the samples of neuroblastoma tissues regardless of the stage of the tumor, whereas significant amplification of ALK was observed in only 1 of 85 cases of human neuroblastoma samples. These data demonstrate the limited frequency of ALK activation in the real progression of neuroblastoma.
Growth Factor Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Tokyo 104-0045, Japan.
Yuko
Y
Osajima-Hakomori
Izumi
I
Miyake
Miki
M
Ohira
Akira
A
Nakagawara
Atsuko
A
Nakagawa
Ryuichi
R
Sakai
D000077548:Anaplastic Lymphoma Kinase; D017209:Apoptosis / Q000502:physiology; D015139:Blotting, Southern; D045744:Cell Line, Tumor; D002675:Child, Preschool; D004789:Enzyme Activation / Q000502:physiology; D005784:Gene Amplification; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007223:Infant; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics*; D009479:Neuropeptides / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D034622:RNA Interference; D020794:Receptor Protein-Tyrosine Kinases; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055765:Shc Signaling Adaptor Proteins; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3
D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; C122029:SHC3 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071427:Src Homology 2 Domain-Containing, Transforming Protein 3; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases