B6.Cg-Cdkn2a^em1Cjs/J

Stock number: 032266
Product name: smArf
Research areas: Cancer Research, Reproductive Biology Research, Sensorineural Research

Description

The mouse Cdkn2a gene encodes two tumor suppressor proteins, p16^Ink4a and p19^Arf. The alternative reading frame (Arf) mRNA carries two translational in-frame start codons. Disruption of the more 5' start codon in this TALEN-derived strain truncates the p19^Arf peptide and drives the use of a second downstream ATG (M45) producing a shorter p15^smArf polypeptide. Expression of the p15^smArf protein corrects developmental defects of Arf-null mice. Mouse embryonic fibroblasts and pro-B lymphocytes from this strain have greatly increased self-renewal capacity and are highly susceptible to oncogenic transformation. This strain continues to express a functional p16^Ink4a polypeptide.

Detailed description

Expression of Cdkn2a (cyclin dependent kinase inhibitor 2A)-encoded alternative reading frame (Arf) protein activates Trp53 in incipient tumor cells that have experienced oncogene activation. The single Arf mRNA encodes two distinct polypeptides: p19^Arf (a tumor suppressor), and N-terminally truncated and unstable p15^smArf ("small mitochondrial Arf").

Deletion of the more 5' start codon in this TALEN-derived strain disrupts the p19^Arf peptide and drives the use of the second downstream ATG (Met-45) producing the p15^smArf peptide. The p15^smArf protein produced by these mice localizes to mitochondria and is deficient as a Trp53-dependent tumor suppressor. Expression of p15^smArf corrects developmental defects of Cdkn2a-coded Arf-null mice (see Stock No. 029676). Specifically, smArf mice have normal sperm counts and vision. smArf mouse embryonic fibroblasts and pro-B cell progenitors, like those of the Arf-null strain, have greatly increased proliferative capacity and are susceptible to oncogenic transformation.

Mice carrying a disruption of p15^smArf and expressing only the p19^Arf peptide are also available (see Stock No. 032270).

Development

RNAs encoding forward and reverse TALEN nucleases were designed to flank the first of two p19^Arf translation initiation codons. The RNAs were injected into C57BL/6J x FVB/N mouse zygotes to generate chimeric founders, from which a 25 bp deletion flanking the more 5' Arf ATG initiation codon was transmitted in the germ line. This mutation forces the use of a second downstream ATG (M45) producing the shorter p15^smArf peptide. This strain was made congenic on a C57BL/6J genetic background by the donating laboratory.

Allele

Symbol: Cdkn2a^em1Cjs
Name: endonuclease-mediated mutation 1, Charles J Sherr
MGI accession ID: MGI:6114043
Generation method: Endonuclease-mediated
Attributes: Modified isoform(s)
Synonyms: p15^smArf
Marker symbol: Cdkn2a
Marker name: cyclin dependent kinase inhibitor 2A
Marker synonyms: Arf; ARF-INK4a; CAI2; CDK4I; CDKN2; CMM2; INK4; INK4A; Ink4a/Arf; INK4a-ARF; MLM; MTS1; MTS-1; P14; P14ARF; P16; p16Cdkn2a; P16INK4; P16INK4A; P19; p19^ARF; P19ARF; Pctr1; TP16
Chromosome: 4
Strain of origin: C57BL/6J x FVB/N
Molecular note: RNAs encoding forward and reverse TALEN nucleases directed to sequences flanking the first Arf ATG translation initiation codon were injected into C57BL/6J ￜ FVB/N mouse zygotes. This resulted in one strain with a 25 bp deletion deleting the ATG and another with a 1 bp deletion immediately downstream of the ATG. Either of these deletions forces the use of the ATG downstream at codon position 45, yielding the shorter p15^smArf peptide. The 25 bp deletion strain was used for further analysis.