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J Biol Chem, Vol. 274, Issue 33, 23358-23367, August 13, 1999
From the Departments of Skin provides an attractive organ system for
exploring coordinated regulation of keratinocyte (KC) proliferation,
differentiation, senescence, and apoptosis. Our main objective was to
determine whether various types of cell cycle arrest confer resistance
to apoptosis. We postulated that KC cell cycle and cell death programs are tightly regulated to ensure epidermal homeostasis. In this report,
simultaneous expression of cyclin-dependent kinase inhibitors (p15,
p16, p21, and p27), a marker of early differentiation (keratin 1),
mediators of apoptosis (caspases 3 and 8), and NF-
Apoptosis in Proliferating, Senescent, and Immortalized
Keratinocytes
,,,
Pathology,
§ Radiation Oncology, and ¶ Medicine, Loyola University
Medical Center, Maywood, Illinois 60153
B were analyzed in
three types of KCs. By comparing the response of proliferating, senescent, and immortalized KCs (HaCaT cells) to antiproliferative agents followed by UV exposure, we observed: 1) Normal KCs follow different pathways to abrupt cell cycle arrest; 2) KCs undergoing spontaneous replicative senescence or confluency predominantly express
p16; 3) Abruptly induced growth arrest, confluency, and senescence
pathways are associated with resistance to apoptosis; 4) The
death-defying phenotype of KCs does not require early differentiation; 5) NF-B is one regulator of resistance to apoptosis; and 6) HaCaT cells have undetectable p16 protein (hypermethylation of the
promoter), dysfunctional NF-B, and diminished capacity to respond to
antiproliferative treatments, and they remain highly sensitive to
apoptosis with cleavage of caspases 3 and 8. These data indicate that
KCs (but not HaCaT cells) undergoing abruptly induced cell cycle arrest or senescence become resistant to apoptosis requiring properly regulated activation of NF-B but not early differentiation.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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