Ras regulates kinesin 13 family members to control cell migration pathways in transformed human bronchial epithelial cells.
We show that expression of the microtubule depolymerizing kinesin KIF2C is induced by transformation of immortalized human bronchial epithelial cells (HBEC) by expression of K-Ras(G12V) and knockdown of p53. Further investigation demonstrates that this is due to the K-Ras/ERK1/2 MAPK pathway, as loss of p53 had little effect on KIF2C expression. In addition to KIF2C, we also found that the related kinesin KIF2A is modestly upregulated in this model system; both proteins are expressed more highly in many lung cancer cell lines compared to normal tissue. As a consequence of their depolymerizing activity, these kinesins increase dynamic instability of microtubules. Depletion of either of these kinesins impairs the ability of cells transformed with mutant K-Ras to migrate and invade matrigel. However, depletion of these kinesins does not reverse the epithelial to mesenchymal transition (EMT) caused by mutant K-Ras. Our studies indicate that increased expression of microtubule destabilizing factors can occur during oncogenesis to support enhanced migration and invasion of tumor cells.
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
E
E
Zaganjor
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
J K
JK
Osborne
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
L M
LM
Weil
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
L A
LA
Diaz-Martinez
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
J X
JX
Gonzales
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
S M
SM
Singel
Hamon Cancer Center for Therapeutic Oncology Research, Dallas, TX, USA.
J E
JE
Larsen
1] Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Hamon Cancer Center for Therapeutic Oncology Research, Dallas, TX, USA.
L
L
Girard
1] Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA [2] Hamon Cancer Center for Therapeutic Oncology Research, Dallas, TX, USA.
J D
JD
Minna
Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
M H
MH
Cobb
D001980:Bronchi / Q000166:cytology; D002283:Carcinoma, Bronchogenic / Q000235:genetics* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic; D003599:Cytoskeleton / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D011905:Genes, ras; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C509805:KIF2A protein, human; C091489:KIF2C protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016547:Kinesins