G2 phase cell cycle arrest in human skin following UV irradiation

Abstract

The contribution of the short wavelength ultraviolet (UV) component of sunlight to the aetiology of skin cancer has been widely acknowledged, although its direct contribution to tumour initiation or progression is still poorly understood. The loss of normal cell cycle controls, particularly checkpoint controls, are a common feature of cancer. UV radiation causes both G1 and G2 phase checkpoint arrest in vitro cultured cells. In this study we have investigated the cell cycle responses to suberythemal doses of UV on skin. We have utilized short-term whole organ skin cultures, and multi parameter immunohistochemical and biochemical analysis to demonstrate that basal and suprabasal layer melanocytes and keratinocytes undergo a G2 phase cell cycle arrest for up to 48 h following irradiation. The arrest is associated with increased p16 expression but no apparent p53 involvement. This type of organ culture provides a very useful model system, combining the ease of in vitro manipulation with the ability to perform detailed molecular analysis in a normal tissue environment. Oncogene (2001) 20, 6103 ± 6110.

Ultraviolet radiation and cutaneous malignant melanoma

“…Interestingly, Gadd45 can be upregulated by UV exposure in a p53-independent fashion through the transcriptional factors Oct-1 and NF-YA (Jin et al, 2000;Takahashi et al, 2001). p53-independent G2 arrest in response to UV also involves a p38 kinase-mediated block in the activation of the mitotic Cdk complexes by cdc25 (Herzinger et al, 1995;Gabrielli et al 1997;Bulavin et al, 2001;Pavey et al, 2001). Recent studies making use of short-term, whole-organ skin cultures have confirmed that basal and suprabasal layer melanocytes and keratinocytes undergo G2 cell cycle arrest in response to suberythemal doses of UV radiation (Pavey et al, 2001).…”

“…However, there are conflicting data on the effect of a-MSH on the growth of melanocytic cells, which may be relevant only to cells in culture (see the review by Thody, 1999). Moreover, UVB is known to induce expression of the cell cycle inhibitor p16INK4a (Pavey et al, 2001), an effect that is potentiated by a-MSH (Pavey and Gabrielli, 2002). An exciting and largely unexplored area of research concerns the stimulation of melanocytes through UVmediated upregulation of growth factors, such as endothelin-1 and bFGF, originating from nonmelanocyte cell types (Archambault et al, 1995;Tada et al, 1998).…”

“…p53-independent G2 arrest in response to UV also involves a p38 kinase-mediated block in the activation of the mitotic Cdk complexes by cdc25 (Herzinger et al, 1995;Gabrielli et al 1997;Bulavin et al, 2001;Pavey et al, 2001). Recent studies making use of short-term, whole-organ skin cultures have confirmed that basal and suprabasal layer melanocytes and keratinocytes undergo G2 cell cycle arrest in response to suberythemal doses of UV radiation (Pavey et al, 2001). While this G2 arrest does not appear to involve p53, it is associated with increased expression of the cell cycle inhibitor p16INK4a.…”

Induction of anion exchanger-1 translation and its opposite roles in the carcinogenesis of gastric cancer cells and differentiation of K562 cells

“…The contribution of nuclear p16 to the G 2 phase arrest is unclear, but studies using in vitro cultured cells have previously demonstrated that p16 inhibits cdk4/cyclin-D activity in the late S/early G 2 phase, which apparently is required for G 2 phase progression. Alternatively, p16 may have a role in constituting a G 1 phase arrest after G 2 arrest (Gabrielli et al, 1999;Pavey et al, 2001).…”

Genetics of melanoma predisposition

“…While it may simply reflect an increased mutational burden that would lead to a higher probability of accumulating sufficient additional mutations required for cancer to develop, it is interesting to contemplate whether a more direct mechanism may also play a role since UVR has been shown to induce p16 expression in human skin (Pavey et al, 1999), where it is involved in a UVRinduced G2 phase cell-cycle block (Pavey et al, 2001). Additionally, there is a tantalizing but not fully understood link to MC1R, since a-MSH has been shown to potentiate p16 expression in human skin after UVR treatment (Pavey et al, 2002).…”