Many Ribosomal Protein Genes Are Cancer Genes in Zebrafish

Abstract

We have generated several hundred lines of zebrafish (Danio rerio), each heterozygous for a recessive embryonic lethal mutation. Since many tumor suppressor genes are recessive lethals, we screened our colony for lines that display early mortality and/or gross evidence of tumors. We identified 12 lines with elevated cancer incidence. Fish from these lines develop malignant peripheral nerve sheath tumors, and in some cases also other tumor types, with moderate to very high frequencies. Surprisingly, 11 of the 12 lines were each heterozygous for a mutation in a different ribosomal protein (RP) gene, while one line was heterozygous for a mutation in a zebrafish paralog of the human and mouse tumor suppressor gene, neurofibromatosis type 2. Our findings suggest that many RP genes may act as haploinsufficient tumor suppressors in fish. Many RP genes might also be cancer genes in humans, where their role in tumorigenesis could easily have escaped detection up to now.

Hematopoietic defects in rps29 mutant zebrafish depend upon p53 activation

“…We wanted to determine the effects of an rps29 insertional mutation[14] on these waves in the zebrafish. Rps29 -/- embryos survive for five days[27], probably due to maternal rps29 protein deposited in the embryo.…”

“…The two fish lines used are: hi2903 , an insertional mutant in the first intron of rps29[14], and p53 M214K/M214K , a p53 point mutant in the DNA-binding domain[22]. …”

“…Ribosomal protein mutants have been generated[14], or these genes can be knocked down in the embryo with morpholino technology. Zebrafish embryos homozygous for ribosomal protein mutations can survive for several days, likely the result of maternal RNA and protein contribution.…”

Aberrant ribosome biogenesis activates c-Myc and ASK1 pathways resulting in p53-dependent G1 arrest

“…The inherited bone marrow failure syndromes representatively showed a close relationship between p53-mediated cell growth regulation and cellular responses to abnormality of ribosome synthesis (Liu and Ellis, 2006). Interestingly, in zebrafish, it was suggested that aberrant ribosome biogenesis through the mutation of ribosomal genes has an oncogenic potential (Amsterdam et al, 2004). In addition, a recent study showed that the enhanced progression of human breast tumor is induced by dysregulation of ribosome biogenesis and translational capacity (Belin et al, 2009).…”

The rise of a ribosomopathy and increased cancer risk

“…Because numerous signaling pathways involved in growth and cell division regulate ribosomal synthesis, numerous other targets could also exist to explain the increased cancer incidence in DBA patients [8]. As a matter of fact, heterozygous mutations in various ribosomal protein genes were recently described in Zebra fish that resulted in peripheral nerve sheath tumors [9]. A schematic view modified from Lipton and Ellis [2] suggests that ribosomal protein genes could act as tumor suppressors (Fig.…”