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Research Article Free access | 10.1172/JCI119382

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

A F Javier, Z Bata-Csorgo, C N Ellis, S Kang, J J Voorhees, and K D Cooper

Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109, USA.

Find articles by Javier, A. in: JCI | PubMed | Google Scholar

Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109, USA.

Find articles by Bata-Csorgo, Z. in: JCI | PubMed | Google Scholar

Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109, USA.

Find articles by Ellis, C. in: JCI | PubMed | Google Scholar

Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109, USA.

Find articles by Kang, S. in: JCI | PubMed | Google Scholar

Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109, USA.

Find articles by Voorhees, J. in: JCI | PubMed | Google Scholar

Department of Dermatology, University of Michigan Medical School, Ann Arbor 48109, USA.

Find articles by Cooper, K. in: JCI | PubMed | Google Scholar

Published May 1, 1997 - More info

Published in Volume 99, Issue 9 on May 1, 1997
J Clin Invest. 1997;99(9):2094–2099. https://doi.org/10.1172/JCI119382.
© 1997 The American Society for Clinical Investigation
Published May 1, 1997 - Version history
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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 beta1 integrin. Rapamycin inhibited the growth of keratinocytes that were leaving quiescence as well as those already in cell cycle without affecting cell viability. Although beta1 integrin(bright) expression was not affected, the number of beta1 integrin(bright) cells entering S/G2/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.

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