Downregulation of 14-3-3sigma prevents clonal evolution and leads to immortalization of primary human keratinocytes.
In human epidermal keratinocytes, replicative senescence, is determined by a progressive decline of clonogenic and dividing cells. Its timing is controlled by clonal evolution, that is, by the continuous transition from stem cells to transient amplifying cells. We now report that downregulation of 14-3-3sigma, which is specifically expressed in human stratified epithelia, prevents keratinocyte clonal evolution, thereby forcing keratinocytes into the stem cell compartment. This allows primary human keratinocytes to readily escape replicative senescence. 14-3-3sigma-dependent bypass of senescence is accompanied by maintenance of telomerase activity and by downregulation of the p16(INK4a) tumor suppressor gene, hallmarks of keratinocyte immortalization. Taken together, these data therefore suggest that inhibition of a single endogenous gene product fosters immortalization of primary human epithelial cells without the need of exogenous oncogenes and/or oncoviruses.
Dellambra
E
E
Laboratory of Tissue Engineering, IDI, Istituto Dermopatico dell'Immacolata, 00040 Rome, Italy.
Golisano
O
O
Bondanza
S
S
Siviero
E
E
Lacal
P
P
Molinari
M
M
D'Atri
S
S
De Luca
M
M
D048948:14-3-3 Proteins; D016475:3T3 Cells; D000818:Animals; D016375:Antisense Elements (Genetics) / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D016922:Cellular Senescence / Q000502:physiology*; D002999:Clone Cells; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015536:Down-Regulation / Q000502:physiology; D000078404:Epidermal Cells; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007621:Karyotyping; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology*; D051379:Mice; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase
D048948:14-3-3 Proteins; D016375:Antisense Elements (Genetics); D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011506:Proteins; D014446:Tyrosine 3-Monooxygenase; D019098:Telomerase