Rapamycin (Sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells

Annabelle F. Javier, Z. Bata-Csörgő, Charles N. Ellis, Sewon Kang, John J. Voorhees, Kevin D. Cooper

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Because the immunosuppressant rapamycin (sirolimus) blocks T cell proliferation in G1 phase, it has been proposed as a potential treatment for psoriasis, a skin disease characterized by T cell activation and keratinocyte stem cell hyperproliferation. To determine another potentially important mechanism through which rapamycin can act as an antipsoriatic agent, we tested its direct effect on keratinocyte stem cell proliferation in vitro as well as in vivo. In vivo cell cycle quiescent (G0 phase) stem cell keratinocytes in primary culture sequentially express de novo cyclin D1 and proliferating cell nuclear antigen (PCNA), prior to S phase entry, and upregulate β1 integrin. Rapamycin inhibited the growth of keratinocytes that were leaving quiescence as well as those already in cell cycle without affecting cell viability. Although β1 integrin(bright) expression was not affected, the number of β1 integrin(bright) cells entering SG/2/M was significantly lowered by rapamycin. Cells treated with rapamycin exhibited decreased PCNA expression while cyclin D1 expression, which precedes PCNA expression in the cell cycle, was not affected. We found similar effects on stem cell keratinocytes in patients with psoriasis treated systemically with rapamycin. Because PCNA is required for cell cycle progression from G1 to S phase, our data indicate that inhibition of PCNA protein synthesis may be an important regulatory element in the ability of rapamycin to exert a G1 block.

Original languageEnglish
Pages (from-to)2094-2099
Number of pages6
JournalJournal of Clinical Investigation
Volume99
Issue number9
Publication statusPublished - May 1 1997

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Proliferating Cell Nuclear Antigen
G1 Phase
Sirolimus
Keratinocytes
Cell Cycle
Stem Cells
Integrins
Cyclin D1
S Phase
Psoriasis
Cell Proliferation
T-Lymphocytes
Cell Cycle Resting Phase
Immunosuppressive Agents
Nuclear Proteins
Skin Diseases
Cell Survival
Up-Regulation
Growth

Keywords

  • keratinocytes
  • PCNA
  • psoriasis

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Rapamycin (Sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. / Javier, Annabelle F.; Bata-Csörgő, Z.; Ellis, Charles N.; Kang, Sewon; Voorhees, John J.; Cooper, Kevin D.

In: Journal of Clinical Investigation, Vol. 99, No. 9, 01.05.1997, p. 2094-2099.

Research output: Contribution to journalArticle

Javier, Annabelle F. ; Bata-Csörgő, Z. ; Ellis, Charles N. ; Kang, Sewon ; Voorhees, John J. ; Cooper, Kevin D. / Rapamycin (Sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. In: Journal of Clinical Investigation. 1997 ; Vol. 99, No. 9. pp. 2094-2099.
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