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The AP-2 family of transcription factors consists of five different proteins in humans and mice: AP-2alpha, AP-2beta, AP-2gamma, AP-2delta and AP-2epsilon. Frogs and fish have known orthologs of some but not all of these proteins, and homologs of the family are also found in protochordates, insects and nematodes. The proteins have a characteristic helix-span-helix motif at the carboxyl terminus, which, together with a central basic region, mediates dimerization and DNA binding. The amino terminus contains the transactivation domain. AP-2 proteins are first expressed in primitive ectoderm of invertebrates and vertebrates; in vertebrates, they are also expressed in the emerging neural-crest cells, and AP-2alpha-/- animals have impairments in neural-crest-derived facial structures. AP-2beta is indispensable for kidney development and AP-2gamma is necessary for the formation of trophectoderm cells shortly after implantation; AP-2alpha and AP-2gamma levels are elevated in human mammary carcinoma and seminoma. The general functions of the family appear to be the cell-type-specific stimulation of proliferation and the suppression of terminal differentiation during embryonic development.
Transcription factor AP-2gamma, a novel marker of gonocytes and seminomatous germ cell tumors
(2005)
Most germ cell tumors (GCTs) arise from intratubular germ cell neoplasias (IGCNUs, also referred to as carcinoma in situ), which are thought to originate from a transformed fetal germ cell, the gonocyte. However, the nature of the molecular pathways involved in IGCNU formation remains elusive. Therefore, identification of novel oncofetal markers is an important prerequisite to further our understanding of the etiology of this tumor entity. In the present study, we show that in humans AP-2gamma is expressed in gonocytes at weeks 12-37 of gestation, indicating a role of this transcription factor in fetal germ cell development. AP-2gamma and c-KIT, a known target of AP-2 transcription factors, were coexpressed in gonocytes, making a direct regulation possible. With increasing differentiation of fetal testis, gradual downregulation of AP-2gamma from the 12th to 37th week of gestation was observed. Furthermore, AP-2gamma was expressed abundantly in 25/25 IGCNUs, 52/53 testicular seminomas, 10/10 metastatic seminomas, 9/9 extragonadal seminomas and 5/5 dysgerminomas. In embryonal carcinomas and choriocarcinomas, focal staining only was observed. Spermatocytic seminomas, teratomas and yolk sac tumors as well as normal adult testis and various control tissues were negative for AP-2gamma. The expression pattern of AP-2gamma, like that of other oncofetal markers, supports the model of a gonocytal origin of IGCNUs and germ cell tumors. Finally, our results provide the basis for applying AP-2gamma immunohistochemistry to the detection of GCT, a tumor entity with a steadily growing incidence in the male population worldwide.
