The survival kinase Mirk/Dyrk1B is a downstream effector of oncogenic K-ras in pancreatic cancer.
The kinase Mirk is overexpressed in many resected pancreatic adenocarcinomas and is amplified in a subset of pancreatic cancer cell lines. Depletion of Mirk has been shown to lead to apoptosis in pancreatic cancer cell lines, and thus to inhibit their clonogenic growth. Mirk is activated by signaling from activated Rac1 to MKK3 in MDCK cells, but the mechanism of activation of Mirk in pancreatic cancers is unknown. In this report, Mirk is shown to be a novel effector of K-ras, a gene mutated in approximately 90% of pancreatic cancers. Activation of Mirk signaling from oncogenic K-ras through Rac1 was shown in transient expression systems and reporter assays. Mirk activation in pancreatic cancer cells was blocked by RNA interference using three different synthetic duplex RNAis to K-ras, or two RNAis to Rac1, by pharmacologic inhibition of Rac1, or by expression of dominant negative K-rasS17N. Rac1 was activated in four out of five pancreatic cancer cell lines, and was activated by signaling from oncogenic K-ras. Mirk knockout does not induce embryonic lethality, and depletion of Mirk had no effect on the survival of normal diploid fibroblasts. In contrast, the clonogenic ability of Panc1 and AsPc1 pancreatic cancer cell lines was reduced 8- to 12-fold by the depletion of Mirk, with a greater reduction seen following the depletion of K-ras or both genes. Mirk is a novel downstream effector of oncogenic K-ras and mediates some of the survival signals activated by ras signaling.
Department of Pathology, Upstate Medical University, State University of New York, Syracuse, New York 13210, USA.
Kideok
K
Jin
Sunju
S
Park
Daina Z
DZ
Ewton
Eileen
E
Friedman
D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D002460:Cell Line; D003114:Colony-Forming Units Assay; D004285:Dogs; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000097603:Dyrk Kinases
D020928:Mitogen-Activated Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D020830:rac1 GTP-Binding Protein; D000097603:Dyrk Kinases