# US 2014/0157444 A1 · Wdr13 as a novel biomarker useful for treating diabetes and cancer

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- Number: US 2014/0157444 A1
- Document ID: US20140157444A1
- Status: Published application
- Kind: A1
- Application number: 14/116,539
- Filed: 2012-04-27
- Published: 2014-06-05
- Earliest claimed: 2011-05-11
- Assignees: Council of Scientific and Industrial Research
- Inventors: Satish Kumar; Vijay Pratap Singh
- Web page: https://patentgrep.com/patent/US20140157444A1

## CPC

- A61K 49/0008: {Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure}
- A01K 67/0276: Knock-out vertebrates
- C07K 14/47: from mammals
- A01K 2217/072: maintaining or altering function, i.e. knock in
- A01K 2227/105: Murine
- A01K 2267/0331: Animal model for proliferative diseases
- A01K 2267/0362: Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
- C07K 2319/41: containing a Myc-tag
- C07K 2319/43: containing a FLAG-tag
- C12N 2710/10043: viral genome or elements thereof as genetic vector
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

WD-repeat proteins are very diverse, yet these are structurally related proteins that participate in a wide range of cellular functions. WDR13, a member of this family, is conserved from fishes to humans and localizes into the nucleus. To understand the in vivo function(s) of Wdr13 gene, we have created and characterized a mutant mouse strain lacking this gene. The mutant mice had higher serum insulin levels and increased pancreatic islet mass as a result of the enhanced beta cell proliferation. While a known cell cycle inhibitor, p21, was down regulated in the mutant islets overexpression of WDR13 in the pancreatic MIN6 cell line resulted in upregulation of p21, accompanied by retardation of cell proliferation. We suggest that WDR13 is a novel negative regulator of the pancreatic beta cell proliferation. Co-immunoprecipitation experiments showed that this protein interacts with estrogen receptors and various HDACs. We provide evidence to show that WDR13 can regulate estrogen receptors-mediated transcription both in HDAC-dependent and HDAC-independent manner. Given the higher insulin levels, better glucose clearance and the lack of insulin resistance in WDR13 deficient mice, we propose that this protein may be a potential candidate drug target for ameliorating impaired glucose metabolism in diabetes.

## Claims

### Claim at position 1

-11. (canceled)

### Claim 12

An expression construct having SEQ ID NO: 2 useful for targeting WDR13 gene represented by SEQ ID NO: 1, the expression construct comprising:
a) Neomycin with polyA as positive selection marker,
b) HSV-tk as negative selection marker,
c) 1.6 kb 5′ homology region for 5′ recombination, and
d) 4.1 kb 3′ homology region for 3′ recombination.

### Claim 13 (depends on 12)

A method of preparing a murine tumor model system comprising:
a) providing SEQ ID NO: 1,
b) preparing a WDR13 targeting construct as claimed in claim 12,
c) introducing the WDR13 targeting construct as claimed in step b into ES cells by electroporation,
d) selecting targeted ES cell clones obtained in step c by Southern blot and
e) generating knockout mice from the targeted ES cell clones obtained in step d.

### Claim 14 (depends on 13)

A tumor model system as claimed in claim 13, useful for studying the progression of cancer at multiple stages.

### Claim 15

A method of treating cancer comprising overexpressing a gene having SEQ ID NO: 1 in cancerous cells.

### Claim 16

A method of treating diabetes and enhancing beta cell proliferation comprising disrupting a gene having SEQ ID NO: 1 in the beta cells.

### Claim 17

A method of regulating beta cell proliferation comprising expressing a protein comprising an amino acid sequence encoded by SEQ ID NO: 1.

### Claim 18

A method of repressing estrogen receptors in a HDAC dependent (ERα) and in a HDAC independent (ERβ) manner comprising expressing a protein comprising an amino acid sequence encoded by SEQ ID NO: 1.

### Claim 19

A method for modulation of beta cells and testicular spermatogonial cells proliferation in vivo comprising disrupting a protein comprising an amino acid sequence encoded by SEQ ID NO: 1.