The human promyelocytic leukemia protein is a tumor suppressor for murine skin carcinogenesis

Abstract

Expression of the PMLRARα fusion dominant-negative oncogene in the epidermis of transgenic mice resulted in spontaneous skin tumors attributed to changes in both the PML and RAR pathways [1]. To determine the contribution of PML to skin tumor susceptibility, transgenic mice were generated on an FVB/N background, that overexpressed the human PML protein in epidermis and hair follicles under the control of the bovine keratin 5 promoter. PML was highly expressed in the epidermis and hair follicles of these mice and was also increased in cultured keratinocytes where it was confined to nuclear bodies. While an overt skin phenotype was not detected in young transgenic mice, expression of keratin 10 (K10) was increased in epidermis and hair follicles and cultured keratinocytes. As mice aged, they exhibited extensive alopecia that was accentuated on the C57BL/6J background. Following skin tumor induction with 7, 12-dimethylbenz[a]anthracene (DMBA) as initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as promoter, papilloma multiplicity and size were decreased in the transgenic mice by 35%, and the conversion of papillomas to carcinomas was delayed. Cultured transgenic keratinocytes underwent premature senescence and upregulated transcripts for p16 and Rb but not p19 and p53. Together, these changes suggest that PML participates in regulating the growth and differentiation of keratinocytes that likely influence its activity as a suppressor for tumor development.

Multi-stage chemical carcinogenesis in mouse skin: Fundamentals and applications

“…Each week record the number of tumors detected as well as the number of mice remaining in the study; document any palpable mass ≥1 mm in size. Tumor volume may also be estimated and recorded periodically 104,105 .

?TROUBLESHOOTING

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PML contributes to p53-independent p21 up-regulation in gamma-irradiation induced DNA damage responses

“…It was originally discovered due to its role as a potent tumor suppressor in the oncogenesis of acute promyelocytic leukemia (APL) [1]. More recent evidence shows that PML acts in other cancers [2], and that PML protein expression is reduced in multiple tumor cell lines [3,4]. In addition, reports indicate that PML is involved in many cellular processes including cell cycle progression, the DNA damage response, transcriptional regulation, viral infection, and apoptosis [5,6].…”

Pten loss in Lgr5+ hair follicle stem cells promotes SCC development

“…The number of tumors per mouse was counted each week as palpable mass >1 mm in size. Tumor volume was also estimated and recorded periodically 16, 18, 19.…”