Loss of Cables, a Cyclin-Dependent Kinase Regulatory Protein, Is Associated with the Development of Endometrial Hyperplasia and Endometrial Cancer

Zukerberg, Lawrence; Debernardo, Robert; Kirley, Sandra D.; D’Apuzzo, Massimo; Lynch, Michael J.; Littell, Ramey D.; Duska, Linda R.; Boring, Landin; Rueda, Bo R.

doi:10.1158/0008-5472.can-03-2833

Cited by 52 publications

(74 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22 Cables is lost in a variety of cancers, including head and neck, lung, endometrial, ovarian, and colon cancers. 13,16,23,24 Our results show that Cables expression is frequently absent in malignant colonic epithelium. Cables expression by immunostaining was decreased or absent in 65% (105 of 160) of primary CRCs.…”

Section: Discussionmentioning

confidence: 56%

“…13 Previous studies found that Cables gene deletion leads to abnormal endometrial epithelial growth in mice. 16 Likewise, in response to a carcinogen (1,2-dimethylhydrazine), Cables Ϫ/Ϫ mice have an increased incidence of colorectal tumors and reduced survival rates compared with Cables ϩ/ϩ mice. 17 Furthermore, primary mouse embryonic fibroblasts from the Cables Ϫ/Ϫ mice show an increased rate of cell proliferation, delayed onset of senescence, and increased growth in low serum concentration.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The Cables Gene on Chromosome 18q Is Silenced by Promoter Hypermethylation and Allelic Loss in Human Colorectal Cancer

Park

Sasaki

Kirley

et al. 2007

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Cables is a cyclin-dependent kinase-binding nuclear protein that maps to chromosome 18q11-12. Here, we assessed Cables expression in 160 colorectal cancers (CRCs), its role in colon cancer cell growth, and the potential mechanisms of Cables inactivation. Expression levels, promoter methylation, and mutational status of Cables were investigated in colon cancer cell lines and primary colon tumors. Chromosome 18q loss of heterozygosity (LOH) was evaluated with multiple polymorphic markers. Cables inhibited cellular proliferation and colony formation in colon cancer cell lines. Colorectal cancer (CRC) is characterized by several unique features that make it well suited for the study of the molecular genetics of tumor progression. A stepwise model of colorectal tumorigenesis has been well defined and validated. 1 The inactivation of the adenomatous polyposis coli tumor suppressor gene is an early event that leads to the development of polyps, followed by oncogenic KRAS mutations in the adenomatous stage. Later events include deletions on chromosome 18q and inactivation of the tumor suppressor gene TP53 on chromosome 17p with the transition to malignancy.Chromosome 18q is lost in a high proportion (approximately 70%) of CRCs. 2 There are many candidate tumor suppressor genes on chromosome 18q, including deleted in colon cancer (DCC), SMAD4 (DPC4), and SMAD2. 3-5 DCC was recently shown to be the netrin-1 receptor. 6 DCC is expressed in normal colonic mucosa and in both primary and metastatic colonic cancer. 7 However, mice lacking the functional DCC gene do not develop colon tumors. 8 The SMAD proteins mediate transforming growth factor-␤ effects and regulate genes involved in cell cycle control. SMAD4 is biallelically inactivated in approximately 60% of pancreatic cancers. 9 However, the number of mutations identified in the SMAD genes has been relatively small in colorectal cancer.

show abstract

Section: Discussionmentioning

confidence: 56%

mentioning

confidence: 99%

The Cables Gene on Chromosome 18q Is Silenced by Promoter Hypermethylation and Allelic Loss in Human Colorectal Cancer

Park

Sasaki

Kirley

et al. 2007

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is located on chromosome 18q11-12, a site frequently deleted in many primary human cancers. Loss of Cables expression was found in greater than 50% of endometrial, 4 colon, 2 lung 5 and ovarian 6 cancers and this correlated with loss of heterozygosity (LOH) on chromosome 18q11-12 in many of these tissues. 2 Stably transfected cultured cell lines that overexpress Cables demonstrated a reduction in cell proliferation compared to cells transfected with a vector control.…”

Section: Introductionmentioning

confidence: 99%

“…Cables -/-mice display endometrial hyperplasia and carcinoma-in-situ at a young age. 4 The Cables -/-mice are also much more prone to the development of colonic tumors following carcinogen treatment. 8 To further investigate Cables as a regulator of the cell cycle and cell proliferation, we compared proliferation, senescence and survival in primary MEFs derived from Cables +/+ and Cables -/-animals.…”

Section: Introductionmentioning

confidence: 99%

Increased growth rate, Delayed senescense and decreased serum dependence characterize cables-deficient cells

Kirley¹,

Rueda²,

Chung³

et al. 2005

Cancer Biology & Therapy

Self Cite

View full text Add to dashboard Cite

Cables (Cables1), a recently described growth suppressor protein that maps to human chromosome 18q11-12, is lost in many primary colon, lung, and gynecological malignancies. Cultured cell lines that overexpress Cables show a reduction in cell proliferation and Cables -/-mice are viable with normal embryonic development. Since Cables expression is lost in primary human tumors and overexpression of Cables suggests a role in growth suppression, we investigated growth properties of primary mouse embryonic fibroblasts (MEFs) from Cables -/-and Cables +/+ mice. Cables -/-MEFs exhibited a doubling time of 43-45 hours compared to 73-75 hours for the Cables +/+ MEFs. Similarly, Cables -/-MEFs show a delayed onset of senescence and extension of lifespan, while the Cables +/+ MEFs ceased proliferating after eight cumulative population doublings. Cables -/-MEFs were able to proliferate in low serum concentrations. These data provide convincing evidence that Cables plays a role in the regulation of cell proliferation and survival.

show abstract

“…31 Previous studies showed that Cables1-null mutant mice displayed increased cellular proliferation (eg, endometrial hyperplasia, colon cancer, and oocyte development). [27][28][29] In contrast to Cables1 loss-of-function mutation, overexpression of Cables1 in a colon cancer cell line showed tumor suppressor activity, including inhibition of colony formation and cell growth. 32 However, there have been no reports that aberrant expression of Cable1 is involved in neural defects in vivo.…”

Section: Truncated Cables1 Causes Acc S Mizuno Et Almentioning

confidence: 95%

Truncated Cables1 causes agenesis of the corpus callosum in mice

Mizuno

Dinh

Mizobuchi

et al. 2014

Laboratory Investigation

View full text Add to dashboard Cite

Agenesis of the corpus callosum (ACC) is a congenital abnormality of the brain structure. More than 60 genes are known to be involved in corpus callosum development. However, the molecular mechanisms underlying ACC are not fully understood. Previously, we produced a novel transgenic mouse strain, TAS, carrying genes of the tetracycline-inducible expression system that are not involved in brain development, and inherited ACC was observed in the brains of all homozygous TAS mice. Although ACC was probably induced by transgene insertion mutation, the causative gene and the molecular mechanism of its pathogenesis remain unclear. Here, we first performed interphase three-color fluorescence in situ hybridization (FISH) analysis to determine the genomic insertion site. Transgenes were inserted into chromosome 18 B12.0 Mb from the centromere. Gene expression analysis and genomic PCR walking showed that the genomic region containing exon 4 of Cables1 was deleted by transgene insertion and the other exons of Cables1 were intact. The mutant allele was designated as Cables1 TAS . Interestingly, Cables1 TAS mRNA consisted of exons 1-3 of Cables1 and part of the transgene that encoded a novel truncated Cables1 protein. Homozygous TAS mice exhibited mRNA expression of Cables1 TAS in the fetal cerebrum, but not that of wild-type Cables1. To investigate whether a dominant negative effect of Cables1 TAS or complete loss of function of Cables1 gives rise to ACC, we produced Cables1-null mutant mice. ACC was not observed in Cables1-null mutant mice, suggesting that a dominant negative effect of Cables1 TAS impairs callosal formation. Moreover, ACC frequency in Cables1 þ /TAS mice was significantly lower than that in Cables1 À /TAS mice, indicating that wild-type Cables1 interfered with the dominant negative effect of Cables1 TAS . This study indicated that truncated Cables1 causes ACC and wild-type Cables1 contributes to callosal formation.

show abstract

Loss of Cables, a Cyclin-Dependent Kinase Regulatory Protein, Is Associated with the Development of Endometrial Hyperplasia and Endometrial Cancer

Cited by 52 publications

References 18 publications

The Cables Gene on Chromosome 18q Is Silenced by Promoter Hypermethylation and Allelic Loss in Human Colorectal Cancer

The Cables Gene on Chromosome 18q Is Silenced by Promoter Hypermethylation and Allelic Loss in Human Colorectal Cancer

Increased growth rate, Delayed senescense and decreased serum dependence characterize cables-deficient cells

Truncated Cables1 causes agenesis of the corpus callosum in mice

Contact Info

Product

Resources

About