The role of BLIMP1 and its putative downstream target TFAP2C in germ cell development and germ cell tumours

Abstract

During the past years, much information has been gathered regarding the genetic and epigenetic programmes leading to the specification and maintenance of primordial germ cells. Expression of the transcriptional regulator BLIMP1 (PRDM1) is regarded as the main event in germ cell specification. BLIMP1 induces a set of target genes, one of them being transcription factor TFAP2C (AP-2γ, Tcfap2c). In murine loss of function models Blimp1 and Tcfap2c share an identical phenotype, strengthening the assumption that they act in the same pathway. One major role of this pathway is the inhibition of somatic differentiation in germ cells. BLIMP1 and TFAP2C are also expressed in carcinoma in situ (CIS, IGCNU, TIN) and in seminoma. As pointed out herein, the presence of both proteins helps to explain the undifferentiated nature of these germ cell tumours. In addition, we performed a meta-analysis of high-throughput datasets searching for TFAP2C/Tcfap2c target genes. This analysis leads us to suggest Nanos3, Dmrt1 and Dnmt3b as potential TFAP2C/Tcfap2c target genes with relevance to germ cell development and germ cell tumours.

Interaction between DMRT1 function and genetic background modulates signaling and pluripotency to control tumor susceptibility in the fetal germ line

“…There is evidence that Dmrt1 and Nanos3 are components of a gene network regulated by the transcription factor Tcfap2c . TCFAP2C/AP-2γ is a downstream target of the master germ cell regulator Blimp1 that is required for specification of germ cells during embryonic development (Schafer et al, 2011; Weber et al, 2010). Based on ChIP and gene expression studies, Tcfap2c is proposed to transcriptionally regulate Nanos3 and Dmrt1 , as well as Dnmt3b (Kidder and Palmer, 2010; Weber et al, 2010; Woodfield et al, 2010).…”

Recent Advances in Understanding the Etiology and Pathogenesis of Pediatric Germ Cell Tumors

“…33,34 AP-2g (TFAP2C) is a transcription factor regulated by BLIMP1 (PRDM gene family), and both factors are expressed in CIS and seminomas in adult testis, and suggested to have a function in repressing somatic differentiation in germ cells. 35,36 In addition to the above-listed pluripotency-related tumor markers, SALL4, a transcription factor involved in the stemness maintenance in various embryonic tissue types and self-renewal in several types of cancers, has been reported as an excellent marker of YST and other GCT components, including even some expression seen in pediatric teratomas. 37 Another transcription factor related to embryonic germ cell differentiation is GATA4, which is variably expressed in a subset of CIS, seminomas, dysgerminomas, and YST.…”

An oncofetal and developmental perspective on testicular germ cell cancer

“…This hypothesis is based on various lines of evidence. Firstly, a number of targeted studies reviewed the marker profile of CIS and different developmental stages of (fetal) germ cells, identifying strong overlap between PGCs and CIS regarding pluripotency and germ cell markers, most notably KIT, POU5F1 NANOG and TCFAP2C (AP-2␥) [68,70,[73][74][75][76][77][78] (Fig. 1B).…”