Molecular mechanisms underlying the MiT translocation subgroup of renal cell carcinomas.

Renal cell carcinomas (RCCs) represent a heterogeneous group of neoplasms, which differ in histological, pathologic and clinical characteristics. The tumors originate from different locations within the nephron and are accompanied by different recurrent (cyto)genetic anomalies. Recently, a novel subgroup of RCCs has been defined, i.e., the MiT translocation subgroup of RCCs. These tumors originate from the proximal tubule of the nephron, exhibit pleomorphic histological features including clear cell morphologies and papillary structures, and are found predominantly in children and young adults. In addition, these tumors are characterized by the occurrence of recurrent chromosomal translocations, which result in disruption and fusion of either the TFE3 or TFEB genes, both members of the MiT family of basic helix-loop-helix/leucine-zipper transcription factor genes. Hence the name MiT translocation subgroup of RCCs. In this review several features of this RCC subgroup will be discussed, including the molecular mechanisms that may underlie their development.

Isolation and characterization of the Xenopus laevis orthologs of the human papillary renal cell carcinoma-associated genes PRCC and MAD2L2 (MAD2B).

Recently we found that the human papillary renal cell carcinoma-associated protein PRCC interacts with the cell cycle control protein Mad2B, and translocates this protein to the nucleus where it exerts its mitotic checkpoint function. Here we have successfully isolated Xenopus laevis Mad2B and PRCC cDNAs. The full-length xMad2B cDNA encodes a 211 amino acid protein that is highly homologous to human Mad2B, thus pointing to an important function for this protein in higher eukaryotes. The full-length xPRCC cDNA encodes a 544 amino acid protein. Remarkably, this protein contains an amino-terminal region distinct from that in mouse and human, whereas the C-terminal region is highly conserved. Northern blot and RT-PCR analyses revealed a relatively low expression of both xMad2B and xPRCC in most tissues examined. However, an abundant expression was observed in testis and oocyte, indicating a role in meiotic division processes. Coimmunoprecipitation and immunofluorescence analyses revealed that, despite its distinct amino terminus, the xPRCC-protein is still capable of interacting with xMad2B and of shuttling this protein to the nucleus. Therefore, the well-established animal model Xenopus laevis can be used as a powerful system to study in detail the role of xPRCC and xMad2B in the intricate processes of cell cycle control.