Many ribosomal protein mutations are associated with growth impairment and tumor predisposition in zebrafish

Lai, Kevin; Amsterdam, Adam; Farrington, Sarah; Bronson, Roderick T.; Hopkins, Nancy; Lees, Jacqueline A.

doi:10.1002/dvdy.21815

Cited by 78 publications

(78 citation statements)

References 34 publications

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“…EIF1 is a translation initiation factor involved in start codon selection (Fraser & Doudna 2007). While little was known about EIF1, other components of protein translation have been implicated in malignant processes involving either TP53 or acting downstream of PI3K/AKT/ MTOR by selectively increasing translation of subsets of mRNAs (Armengol et al 2007, MacInnes et al 2008, Sonenberg 2008, Chakraborty et al 2009, Lai et al 2009). Furthermore, EEF1A protein levels were increased in breast tumors with high proteasome activity (Chen & Madura 2005).…”

Section: Discussionmentioning

confidence: 99%

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Agthoven¹,

Sieuwerts²,

Meijer³

et al. 2010

Endocrine-Related Cancer

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Although endocrine treatment of breast cancer is effective and common practice, in advanced disease the development of resistance is nearly inevitable. To get more insight into individual genes that account for resistance against hormonal agents, we have executed functional genetic screens and subsequently evaluated the clinical relevance of several identified genes with respect to tumor aggressiveness and tamoxifen resistance in estrogen receptor-positive patients. Estrogen-dependent human breast cancer cells were transduced with different retroviral cDNA expression libraries and subjected to selective cultures with various anti-estrogens. From a total of 264 resistant cell clones, 132 different genes were recovered by PCR. By applying stringent selection criteria, we identified 15 breast cancer anti-estrogen resistance (BCAR) genes individually yielding resistance. BCAR genes were recovered with differential frequencies for the diverse culture conditions and anti-estrogen drugs. Analysis of the relation of BCAR genes (EIF1, FBXL10, HRAS, NRG1, PDGFRA, PDGFRB, RAD21, and RAF1) with tamoxifen treatment in patients with advanced disease showed significant association with clinical benefit and progression-free survival for EIF1 and PDGFRA mRNA levels. Furthermore, PDGFRA and HRAS mRNA levels were significantly associated with tumor aggressiveness in lymph node-negative patients who had not received adjuvant systemic therapy. In conclusion, our functional genetic screens showed that BCAR genes differ in their ability to confer resistance towards distinct antiestrogens. Based on the clinical relevance of several BCAR genes, further studies are warranted to characterize the underlying mechanisms, which may ultimately lead to the development of novel treatments and more individualized management of breast cancer patients.

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Section: Discussionmentioning

confidence: 99%

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Agthoven¹,

Sieuwerts²,

Meijer³

et al. 2010

Endocrine-Related Cancer

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show abstract

“…A largescale insertional mutagenesis screen identified 11 fish lines containing heterozygous mutations in RPs that showed elevated rates of malignant peripheral nerve sheath tumors, suggesting that some RPs may act as haploinsufficient tumor suppressors (Amsterdam et al, 2004). Follow-up anlayses of 28 heterozygous RP mutant lines revealed that only a fraction of the lines were predisposed to malignant peripheral nerve sheath tumors, but those with the tumor development phenotype also showed a growth impairment defect (Lai et al, 2009). Interestingly, development of malignant peripheral nerve sheath tumors was shown to be, in part, dependent on loss of p53 (Berghmans et al, 2005).…”

Section: Rp Imbalances Activate P53mentioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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“…A retroviral mutagenesis screen in zebrafish had identified a mutagenic insertion in the rpl3 locus, rpl3 hi2347 Lai et al, 2009). We therefore examined pancreatic development at 72 hpf in progeny of an incross of rpl3 hi2347/+ ;ptf1a:eGFP;ins:mCherry adults.…”

Section: Loss Of Sbds Is Associated With a Broad Change In Ribosome-rmentioning

confidence: 99%

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

et al. 2012

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SUMMARYMutations in the human Shwachman-Bodian-Diamond syndrome (SBDS) gene cause defective ribosome assembly and are associated with exocrine pancreatic insufficiency, chronic neutropenia and skeletal defects. However, the mechanism underlying these phenotypes remains unclear. Here we show that knockdown of the zebrafish sbds ortholog fully recapitulates the spectrum of developmental abnormalities observed in the human syndrome, and further implicate impaired proliferation of ptf1a-expressing pancreatic progenitor cells as the basis for the observed pancreatic phenotype. It is thought that diseases of ribosome assembly share a p53-dependent mechanism. However, loss of p53 did not rescue the developmental defects associated with loss of zebrafish sbds. To clarify the molecular mechanisms underlying the observed organogenesis defects, we performed transcriptional profiling to identify candidate downstream mediators of the sbds phenotype. Among transcripts displaying differential expression, functional group analysis revealed marked enrichment of genes related to ribosome biogenesis, rRNA processing and translational initiation. Among these, ribosomal protein L3 (rpl3) and pescadillo (pes) were selected for additional analysis. Similar to knockdown of sbds, knockdown or mutation of either rpl3 or pes resulted in impaired expansion of pancreatic progenitor cells. The pancreatic phenotypes observed in rpl3-and pes-deficient embryos were also independent of p53. Together, these data suggest novel p53-independent roles for ribosomal biogenesis genes in zebrafish pancreas development.

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Many ribosomal protein mutations are associated with growth impairment and tumor predisposition in zebrafish

Cited by 78 publications

References 34 publications

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Selective recruitment of breast cancer anti-estrogen resistance genes and relevance for breast cancer progression and tamoxifen therapy response

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

Ribosomal biogenesis genes play an essential and p53-independent role in zebrafish pancreas development

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