Morphological transformation induced by activation of the mitogen-activated protein kinase pathway requires suppression of the T-type Ca2+ channel

Transformation of fibroblasts by various oncogenes, including ras, mos, and src accompanies with characteristic morphological changes from flat to rou nd (or spindle) shapes, Such morphological change is believed to play an im portant role in establishing malignant characteristics of cancer cells. Act ivation of the mitogen-activated protein kinase (MAPR) pathway is a converg ing downstream event of transforming activities of many oncogene products c ommonly found in human cancers. Intracellular calcium is known to regulate cellular morphology, In fibroblasts, Ca2+ influx is primarily controlled by two types of Ca2+ channels (T- and L-types), Here, we report that the T-ty pe current was specifically inhibited in cells expressing oncogenically act ivated Ras as well as gain-of-function mutant MEK (MAPK/extracellular signa l-regulated kinase (ERK) kinase, a direct activator of MAPK), whereas treat ment of ras-transformed cells with a MEK-specific inhibitor restored T-type Ca2+ channel activity. Using a T-type Ca2+ channel antagonist, we further found that suppression of the T-type Ca2+ channel by the activated MAPK pat hway is a prerequisite event for the induction and/or maintenance of transf ormation-associated morphological changes.