The Paternal Gene of the DDK Syndrome Maps to the <i>Schlafen</i> Gene Cluster on Mouse Chromosome <i>11</i>

Bell, Timothy A.; Casa-Esperón, Elena de la; Doherty, Heather E.; Ideraabdullah, Folami Y.; Kim, Kuikwon; Wang, Yunfei; Lange, Leslie A.; Wilhemsen, Kirk; Lange, Ethan M.; Sapienza, Carmen; Villena, Fernando Pardo Manuel de

doi:10.1534/genetics.105.047118

Cited by 34 publications

(54 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In general, patients with recurrent or advanced disease have limited treatment options and a very poor overall prognosis (7). The Schlafen (SLFN) family of genes includes several members that share structural homology and play regulatory roles in the control of cell cycle progression and cell growth arrest (8)(9)(10)(11)(12). There are several human and mouse genes that are members of the SLFN family (9,11).…”

mentioning

confidence: 99%

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

Sassano

Mavrommatis

Arslan

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

We provide evidence that human SLFN5, an interferon (IFN)-inducible member of the Schlafen (SLFN) family of proteins, exhibits key roles in controlling motility and invasiveness of renal cell carcinoma (RCC) cells. Our studies define the mechanism by which this occurs, demonstrating that SLFN5 negatively controls expression of the matrix metalloproteinase 1 gene (MMP-1), MMP-13, and several other genes involved in the control of malignant cell motility. Importantly, our data establish that SLFN5 expression correlates with a better overall survival in a large cohort of patients with RCC. The inverse relationship between SLFN5 expression and RCC aggressiveness raises the possibility of developing unique therapeutic approaches in the treatment of RCC, by modulating SLFN5 expression. Interferons (IFNs) are cytokines with important antineoplastic activities and therefore are frequently utilized in the treatment of cancer (1-4). A malignancy that exhibits sensitivity to interferon treatment is renal cell carcinoma (RCC) (5). RCC is the most common type of kidney tumor in humans and is associated with high morbidity and mortality (6, 7). In general, patients with recurrent or advanced disease have limited treatment options and a very poor overall prognosis (7). The Schlafen (SLFN) family of genes includes several members that share structural homology and play regulatory roles in the control of cell cycle progression and cell growth arrest (8-12). There are several human and mouse genes that are members of the SLFN family (9, 11). Prior evidence has implicated members of the Schlafen family in the regulation of tumorigenesis (13)(14)(15)(16)(17)(18). Notably, expression of various members of this family is upregulated following treatment with type I IFNs (17-19), cytokines known to promote induction of antineoplastic, antiviral, and immunoregulatory effects (1-4). Despite the induction of human and mouse SLFN genes by IFNs, the precise mechanisms by which SLFNs mediate antineoplastic responses in different types of malignant human cells remain to be determined.In the present study, we provide evidence that the expression of human SLFN5 is inducible by type I IFN receptor. SLFN5, like other long SLFNs, is characterized by a large C-terminal extension, a DNA/RNA helicase domain, and a nuclear localization sequence (NLS) (9, 20). Although SLFN5 is induced in melanoma cells following IFN treatment (18), the role of SLFN5 in tumor progression is largely unknown.In efforts to define the functional implications of SLFN5 expression in malignant RCC cells, we found that SLFN5 repressed the motility and invasiveness of malignant renal cell carcinoma cells, by negatively controlling the expression of matrix metalloproteinase (MMP) genes, such as MMP-1 and MMP-13. Importantly, analysis of SLFN5 mRNA expression in a large number of samples from a cohort of RCC patients demonstrated that SLFN5 expression correlates with better overall survival of RCC patients. Altogether, our studies for the first time establish a mechanism by which...

show abstract

mentioning

confidence: 99%

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

Sassano

Mavrommatis

Arslan

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…In summary, the Slfn genes have expanded and diversified during the mammalian evolution, and are located in an unstable and rapidly changing region, specially in mouse and other rodents, where they could still be evolving fast (3,5). Moreover, there is evidence of positive selection in the four groups, especially in groups 1 and 4.…”

Section: Number Characteristics and Genomic Location Of The Schlafenmentioning

confidence: 95%

“…However, further data will be necessary to confirm the existence of functional protein products (2,3,5) (Figure 2). Interestingly, comparative analysis among genetically diverse mouse inbred strains has shown the presence of large insertions/deletions that include some Slfn members (5,8), such as Slfn8 (de la Casa-Esperon and Sapienza, unpublished data). Therefore, and specially in rodents (see Slfn evolution section below), the possibility of copy number variation among individuals/strains must be taken into account in many Slfn studies.…”

Section: Number Characteristics and Genomic Location Of The Schlafenmentioning

confidence: 99%

“…This lethal phenotype is the result of the interaction of a factor provided by the sperm with a maternal cytoplasmic product present in the DDK oocytes (22)(23)(24)(25). Both genes, the maternal and the paternal, map to the Om (Ovum mutant) region, which contains the Slfn genes; among them, LOC435271 is the stronger candidate for the paternal incompatible allele responsible of the DDK syndrome (4,5,(26)(27)(28)(29)(30). Interestingly, a second phenotype was observed in the Om region: unequal segregation of chromatids during the second meiotic division in mouse eggs (meiotic drive).…”

Section: Expression and Phenotypes Associated To The Mammalian Schlafmentioning

confidence: 99%

“…Subsequently, Slfn5, Slfn8, Slfn9 and Slfn10 were discovered in mouse (4) (Figure 1). In addition, other paralogous sequences (LOC435271 and Slfn14) have been identified (2,3,5) (Figure 2). The SLFN1-10 proteins display a strong similarity (51%-96%) over a common shared region (3) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

From mammals to viruses: the Schlafen genes in developmental, proliferative and immune processes

Casa-Esperón

2011

BioMolecular Concepts

View full text Add to dashboard Cite

The Schlafen genes have been associated with proliferation control and with several differentiation processes, as well as with disparate phenotypes such as immune response, embryonic lethality and meiotic drive. They constitute a gene family with widespread distribution in mammals, where they are expressed in several tissues, predominantly those of the immune system. Moreover, horizontal transfer of these genes to orthopoxviruses suggests a role of the viral Schlafens in evasion to the host immune response. The expression and functional studies of this gene family will be reviewed under the prism of their evolution and diversification, the challenges they pose and the future avenues of research.

show abstract

Characterization of two Mst1‐deficient mouse models

Anguera¹,

Liu²,

Avruch³

et al. 2008

Developmental Dynamics

View full text Add to dashboard Cite

Mammalian sterile 20-like kinase 1 (Mst1) is a ubiquitously expressed serine/threonine kinase belonging to the family of Sterile 20-like kinases. MST1 has been inferred to play important roles in apoptosis and in the inhibition of proliferation in mammalian cells. Here, we describe the genetic characterization of Mst1-deficient mice produced by two distinct gene-trap insertions. Animals generated from clone RRT293 exhibit transmission ratio distortion favoring the mutated allele and is amplified with each generation. Inexplicably, while the mutated allele is favored for transmission, its homozygosity is embryonic lethal. By contrast, animals generated from the second Mst1 gene-trap clone, AJ0315, do not show any gross abnormalities. We find that the discrepancy in phenotype is most likely attributable to a second insertion in the RRT293 clone. Thus, a mutation in Mst1 alone does not affect survival. Our results set the stage for identification of the lethal second-site mutation that is paradoxically favored for transmission.

show abstract

The Paternal Gene of the DDK Syndrome Maps to the Schlafen Gene Cluster on Mouse Chromosome 11

Cited by 34 publications

References 40 publications

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

Human Schlafen 5 (SLFN5) Is a Regulator of Motility and Invasiveness of Renal Cell Carcinoma Cells

From mammals to viruses: the Schlafen genes in developmental, proliferative and immune processes

Characterization of two Mst1‐deficient mouse models

Contact Info

Product

Resources

About