Mirk/Dyrk1B in cancer.
Mirk/Dyrk1B is a member of a conserved family of serine/threonine kinases which are activated by intramolecular tyrosine phosphorylation, and which mediate differentiation in different tissues-Mirk in skeletal muscle, Dyrk1A in the brain, etc. One role of Mirk in skeletal muscle differentiation is to block cycling myoblasts in the G0 quiescent state by modification of cell cycle regulators, while another role of Mirk is to limit apoptosis in fusing myoblasts. Amplification of the Mirk gene, upregulation of Mirk expression and/or constitutive activation of this kinase have been observed in several different types of cancer. If coupled with a stress condition such as serum starvation which induces a quiescent state, depletion of Mirk by RNA interference using either synthetic duplex RNAi's or pSilencer-encoded RNAi's have decreased colony formation of different cancer cell lines and enhanced apoptosis induced by chemotherapeutic drugs. Mirk is activated by phosphorylation by the stress-activated SAPK kinases MKK3 and MKK6. Our working hypothesis is that Mirk is activated by this pathway in response to various stresses, and then acts as a checkpoint kinase to arrest damaged tumor cells in a quiescent state and allow cellular repair. Pharmacological inhibition of Mirk may enhance the anti-tumor effect of chemotherapeutic drugs.
Friedman
Eileen
E
Pathology Department, Upstate Medical University, State University of New York, 750 East Adams Street, Syracuse, New York, USA. friedmae@upstate.edu
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D009154:Mutation; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000097603:Dyrk Kinases
D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D000097603:Dyrk Kinases; C482566:MAP2K6 protein, human