Immortalization of primary human keratinocytes by the helix-loop-helix protein, Id-1.
Basic helix-loop-helix (bHLH) DNA-binding proteins have been demonstrated to regulate tissue-specific transcription within multiple cell lineages. The Id family of helix-loop-helix proteins does not possess a basic DNA-binding domain and functions as a negative regulator of bHLH proteins. Overexpression of Id proteins within a variety of cell types has been shown to inhibit their ability to differentiate under appropriate conditions. We demonstrate that ectopic expression of Id-1 leads to activation of telomerase activity and immortalization of primary human keratinocytes. These immortalized cells have a decreased capacity to differentiate as well as activate phosphorylation of the retinoblastoma protein. Additionally, these cells acquire an impaired p53-mediated DNA-damage response as a late event in immortalization. We conclude that bHLH proteins play a pivotal role in regulating normal keratinocyte growth and differentiation, which can be disrupted by the immortalizing functions of Id-1 through activation of telomerase activity and inactivation of the retinoblastoma protein.
Alani
R M
RM
Department of Pathology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Hasskarl
J
J
Grace
M
M
Hernandez
M C
MC
Israel
M A
MA
Münger
K
K
D020134:Catalytic Domain; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1; D015603:Keratinocytes / Q000187:drug effects*; D010766:Phosphorylation; D012313:RNA; D012097:Repressor Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D014157:Transcription Factors / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004268:DNA-Binding Proteins; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase