Hyperproliferation, induction of c-Myc and 14-3-3sigma, but no cell fragility in keratin-10-null mice.
In the past, keratins have been established as structural proteins. Indeed, mutations in keratin 10 (K10) and other epidermal keratins lead to severe skin fragility syndromes. Here, we present adult K10-/- mice, which reveal a novel connection between the regulation of cell proliferation and K10. Unlike most keratin mutant mice, the epidermis of adult K10-/- mice showed no cytolysis but displayed hyperproliferation of basal keratinocytes and an increased cell size. BrdU labelling revealed a shortened transition time for keratinocytes migrating outwards and DAPI staining of epidermal sheets uncovered an impaired organization of epidermal proliferation units. These remarkable changes were accompanied by the induction of c-Myc, cyclin D1, 14-3-3sigma and of wound healing keratins K6 and K16. The phosphorylation of Rb remained unaltered. In line with the downregulation of K10 in squamous cell carcinomas and its absence in proliferating cells in vivo, our data suggest that the tissue-restricted expression of some members of the keratin gene family not only serves structural functions. Our results imply that the altered composition of the suprabasal cytoskeleton is able to alter the proliferation state of basal cells through the induction of c-Myc. A previous model based on transfection of K10 in immortalized human keratinocytes suggested a direct involvement of K10 in cell cycle control. While those experiments were performed in human cultured keratinocytes, our data establish, that in vivo, K10 acts by an indirect control mechanism in trans.
Reichelt
Julia
J
Institute of Physiological Chemistry and Bonner Forum Biomedizin, University of Bonn, Nussallee 11, 53115 Bonn, Germany.
Magin
Thomas M
TM
D048948:14-3-3 Proteins; D000818:Animals; D014408:Biomarkers, Tumor; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics*; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005092:Exonucleases / Q000235:genetics / Q000378:metabolism*; D005095:Exoribonucleases; D005786:Gene Expression Regulation / Q000235:genetics; D017488:Hyperkeratosis, Epidermolytic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006984:Hypertrophy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053550:Keratin-10; D053553:Keratin-6; D007633:Keratins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012873:Skin Diseases, Genetic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; C507493:KRT10 protein, human; C507569:KRT6A protein, human; C507570:KRT6B protein, human; C507571:KRT6C protein, human; D053553:Keratin-6; C507491:Krt10 protein, mouse; C507567:Krt6a protein, mouse; C507568:Krt71 protein, mouse; C489427:MYC protein, human; C489428:Myc protein, mouse; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D053550:Keratin-10; D007633:Keratins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human