title: Novel function of keratins 5 and 14 in proliferation and differentiation of stratified epithelial cells.
abstract: Keratins are cytoplasmic intermediate filament proteins preferentially expressed by epithelial tissues in a site-specific and differentiation-dependent manner. The complex network of keratin filaments in stratified epithelia is tightly regulated during squamous cell differentiation. Keratin 14 (K14) is expressed in mitotically active basal layer cells, along with its partner keratin 5 (K5), and their expression is down-regulated as cells differentiate. Apart from the cytoprotective functions of K14, very little is known about K14 regulatory functions, since the K14 knockout mice show postnatal lethality. In this study, K14 expression was inhibited using RNA interference in cell lines derived from stratified epithelia to study the K14 functions in epithelial homeostasis. The K14 knockdown clones demonstrated substantial decreases in the levels of the K14 partner K5. These cells showed reduction in cell proliferation and delay in cell cycle progression, along with decreased phosphorylated Akt levels. K14 knockdown cells also exhibited enhanced levels of activated Notch1, involucrin, and K1. In addition, K14 knockdown AW13516 cells showed significant reduction in tumorigenicity. Our results suggest that K5 and K14 may have a role in maintenance of cell proliferation potential in the basal layer of stratified epithelia, modulating phosphatidylinositol 3-kinase/Akt-mediated cell proliferation and/or Notch1-dependent cell differentiation.
authors: Advanced Centre for Treatment, Research & Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India.
authors: Hunain
authors: H
authors: Alam
authors: Lalit
authors: L
authors: Sehgal
authors: Samrat T
authors: ST
authors: Kundu
authors: Sorab N
authors: SN
authors: Dalal
authors: Milind M
authors: MM
authors: Vaidya
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002448:Cell Adhesion; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007399:Interphase; D053547:Keratin-14 / Q000235:genetics / Q000378:metabolism*; D053555:Keratin-5 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; C507540:KRT14 protein, human; C503940:KRT5 protein, human; D053547:Keratin-14; D053555:Keratin-5; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D051057:Proto-Oncogene Proteins c-akt