ABSTRACT. 3-methylcholanthrene (MC)-induced mouse 10 embryonal (ERSs) and 24 pleomorphic rhabdomyosarcomas (PRSs) of the dermis were examined immunohistochemically for nuclear reactivity of Mdm2, p53, and proliferating cell nuclear antigen (PCNA). ERSs were microscopically present in the rhabdium layer of the dermis from 10 to 13 weeks post injection (PI), and PRSs developed from 13 weeks PI. Moderate to marked Mdm2 reactivity was observed in each of the 10 ERSs, and 23 of the 24 PRSs. Moderate to marked p53 reactivity was observed in 5 of the 10 ERSs, and 19 of the 24 PRSs. p53 reactivity increased in PRSs compared with ERSs. The level of Mdm2 expression was significantly higher compared with p53 expression. Discordant Mdm2 overexpression was observed in 5 ERSs and 5 PRSs, and discordant p53 overexpression was observed in 1 PRSs, although co-overexpression of Mdm2 and p53 was observed in 5 ERSs and 18 PRSs. PCNA reactivity significantly increased in PRSs compared with ERSs. These results suggest that Mdm2 overexpression is an important pathogenic event in MC-induced mouse rhabdomyosarcomas, and its expression may be induced by p53-independent pathway. KEY WORDS: MC, Mdm2, mouse, p53, rhabdomyosarcoma.J. Vet. Med. Sci. 68 (5): [427][428][429][430][431] 2006 The Mdm2 oncogene was first identified as an amplified gene on a murine double-minute chromosome in the 3T3DM cell line, a spontaneously transformed derivative of BALB/c 3T3 cells [3]. Mdm2 has been shown to interact with a group of cell cycle-related proteins, including the retinoblastoma protein [29], E2F1 and DP1 transcription factors [14], and transforming growth factor-beta [23]. Mdm2 overexpression is frequent in soft tissue and bone tumors in human beings [2,8,13,30] and dogs [16,22].The tumor suppressor gene p53 plays a key role in the control of the cell cycle, maintenance of genomic stability, and programmed cell death [12,27]. p53 mutations are common in methylcholanthrene-induced mouse tumors [4], and have been identified in several types of human neoplasms [18,21]. The Mdm2 protein directly binds to p53 protein and inhibits the transcriptional function of p53 protein and also targets it for degradation via the ubiquitin-proteasome pathway [15,27].Rhabdomyosarcoma is the most common malignant soft tissue sarcoma in childhood and adolescence. Recently, it has been reported that Mdm2 is expressed at low levels and does not show differences between subtypes of rhabdomyosarcomas of human beings [11,24,25]. However, little is known about the mechanism of tumorigenesis of rhabdomyosarcoma. Expression of Mdm2 and p53 has not been investigated in methylcholanthrene-induced rhabdomyosarcomas, although expression of some differentiation markers such as vimentin, desmin, and myoglobin has been studied [9,26]. Thirty-four rhabdomyosarcomas were induced by subcutaneous injection of 3-methylcholanthrene (MC) in C3H/HeJ mice. In this study, we examined nuclear reactivity of Mdm2 and p53 proteins by immunohistochemistry in MC-induced mouse rhabdomyosarcomas, a...