Original paper

Archives of Dermatological Research

, Volume 293, Issue 9, pp 460-469

First online:

Cells derived from tuberous sclerosis show a prolonged S phase of the cell cycle and increased apoptosis

  • M. Wataya-KanedaAffiliated withDepartment of Dermatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan e-mail: mkaneda@derma.med.osaka-u.ac.jp, Tel.: +81-6-8793031, Fax: +81-6-8793039,
  • , Yasufumi KanedaAffiliated withDivision of Gene Therapy Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565, Japan
  • , Okio HinoAffiliated withDepartment of Experimental Pathology, Cancer Institute, Tokyo, Japan
  • , Hiroyuki AdachiAffiliated withDepartment of Experimental Pathology, Cancer Institute, Tokyo, Japan
  • , Youko HirayamaAffiliated withDepartment of Experimental Pathology, Cancer Institute, Tokyo, Japan
  • , Kuniaki SeyamaAffiliated withDepartment of Respiratory Medicine, Juntendo University, School of Medicine, Juntendo, Japan
  • , Teruhiko SatouAffiliated withDepartment of Respiratory Medicine, Juntendo University, School of Medicine, Juntendo, Japan
  • , Kunihiko YoshikawaAffiliated withDepartment of Dermatology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita City, Osaka 565-0871, Japan e-mail: mkaneda@derma.med.osaka-u.ac.jp, Tel.: +81-6-8793031, Fax: +81-6-8793039,

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Abstract Tuberous sclerosis complex (TSC) is a multisystemic disorder characterized by systemic hamartomas. Although the disease-determining genes TSC1 and TSC2 have been isolated, the molecular pathogenesis of the disease is not understood. We examined cell cycle abnormalities in skin specimens and cultured cells derived from specific lesions of TSC patients with confirmed TSC1 or TSC2 mutations. None of the specimens used in this study showed loss of heterozygosity (LOH). We detected more cells positive for PCNA and fewer cells positive for MPP2 in the epidermis of TSC patients than in the epidermis of control patients without TSC. Incorporation of 5-bromo-2-deoxyuridine (BrdU) was similar in fibroblasts derived from TSC lesions and in normal human fibroblasts. These results suggest that the cell cycle of TSC cells shows a prolonged S phase. Flow cytometric analysis confirmed S phase prolongation in TSC cells. Many apoptotic cells were detected by a nick end labeling assay in both skin tissue and cultured fibroblasts derived from specific TSC lesions. Examination of cyclin levels showed increased nuclear cyclin A and cytoplasmic cyclin B and decreased nuclear cdc2 levels. We conclude that suppression of either TSC1 or TSC2 may change cyclin levels, prolong S phase and induce apoptotic cell death.

Keywords Tuberous sclerosis complex (TSC) Proliferating cell nuclear antigen (PCNA) MPM2 reactive phosphoprotein (MPP2) Cyclin-dependent kinase 1 (P34cdc2 or cdc2) Loss of heterozygosity (LOH)