Abstract
Several lines of evidence have revealed that newly emerging transformed cells are often eliminated from the epithelium, though the underlying molecular mechanisms of this cancer preventive phenomenon still remain elusive. In this study, using mammalian cell culture systems we have identified plectin, a versatile cytoskeletal linker protein, as a novel regulator for apical extrusion of RasV12-transformed cells. Plectin is accumulated in RasV12 cells when they are surrounded by normal epithelial cells. Similarly, cytoskeletal proteins tubulin, keratin, and Epithelial Protein Lost In Neoplasm (EPLIN) are also accumulated in the transformed cells surrounded by normal cells. Knockdown or functional disruption of one of these molecules diminishes the accumulation of the others, indicating that the accumulation process of the individual protein mutually depends on each other. Furthermore, plectin-knockdown attenuates caveolin-1 (Cav-1) enrichment and PKA activity in RasV12 cells and profoundly suppresses the apical extrusion. These results indicate that the plectin-microtubules-EPLIN complex positively regulates apical elimination of RasV12-transformed cells from the epithelium in a coordinated fashion. Further development of this study would open a new avenue for cancer preventive medicine.
Highlights
In most of the multicellular organisms such as fly and mammals, oncogenic mutations occur within the epithelial tissues at the initial stage of carcinogenesis, though the fate of the transformed cells remained enigmatic
Using tetracycline-inducible RasV12-expressing Madin-Darby canine kidney (MDCK) cells we demonstrated that the amount of immunoprecipitated plectin with anti-phospho-tyrosine antibodies was increased under the mix culture of normal and RasV12-transformed cells, compared with single culture of normal or RasV12-transformed cells (Fig. 1a,b)
We found that tubulin, a major component of microtubules, was accumulated in the apical region of RasV12-transformed cells that were surrounded by normal cells, which was partially co-localized with plectin (Fig. 3a)
Summary
In most of the multicellular organisms such as fly and mammals, oncogenic mutations occur within the epithelial tissues at the initial stage of carcinogenesis, though the fate of the transformed cells remained enigmatic. Recent studies by us and others, have revealed that the newly emerging transformed cells are often eliminated from the epithelium. During this process, normal and transformed epithelial cells compete with each other for survival, a process called cell competition[1,2,3,4,5,6,7,8,9,10]. Plectin is a versatile cytoskeletal linker protein of high molecular weight (>5 00 kDa)[15,16,17,18] It binds to a number of cytoskeletal proteins including microtubules and intermediate filaments and is involved in establishment and dynamic modulation of the cytoskeletal network. We have identified plectin as a new player acting in the apical extrusion of RasV12-transformed cells
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