MicroRNA 203 expression in keratinocytes is dependent on regulation of p53 levels by E6.
A screen of microRNA (miRNA) expression following differentiation in human foreskin keratinocytes (HFKs) identified changes in several miRNAs, including miRNA 203 (miR-203), which has previously been shown to play an important role in epithelial cell biology by regulating p63 levels. We investigated how expression of human papillomavirus type 16 (HPV16) oncoproteins E6 and E7 affected miR-203 expression during proliferation and differentiation of HFKs. We demonstrated that miR-203 expression is reduced in HFKs where p53 function is compromised, either by the viral oncoprotein E6 or by knockout of p53 using short hairpin RNAs (p53i). We show that the induction of miR-203 observed during calcium-induced differentiation of HFKs is significantly reduced in HFKs expressing E6 and in p53i HFKs. Induction of miR-203 in response to DNA damage is also reduced in the absence of p53. We report that proliferation of HFKs is dependent on the level of miR-203 expression and that overexpression of miR-203 can reduce overproliferation in E6/E7-expressing and p53i HFKs. In summary, these results indicate that expression of miR-203 is dependent on p53, which may explain how expression of HPV16 E6 can disrupt the balance between proliferation and differentiation, as well as the response to DNA damage, in keratinocytes.
McKenna
Declan J
DJ
Centre for Cancer Research and Cell Biology, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, United Kingdom.
McDade
Simon S
SS
Patel
Daksha
D
McCance
Dennis J
DJ
D001483:Base Sequence; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000502:physiology; D052162:Human papillomavirus 16 / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; C068651:E6 protein, Human papillomavirus type 16; C546703:MIRN203 microRNA, human; D035683:MicroRNAs; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C059731:oncogene protein E7, Human papillomavirus type 16