Sci. Aging Knowl. Environ., 26 February 2003
Vol. 2003, Issue 8, p. tg4
GENETICALLY ALTERED MICE
p66Shc-/- Mice (Shc1tm1Pgp Mice)
||p66Shc-/- mice (Shc1tm1Pgp mice)
||129/Sv strain; p66Shc+/- heterozygous parents were bred for experiments.
||p66shc (src homology 2 domain-containing transforming protein C1) gene (also known as p66 and ShcA)
|Type of change
||Insertion of a vector for a targeted mutation of the wild-type CH2 exon.
|Nature of protein
||There are three ShcA proteins, which are characterized by an SH2 domain at the carboxy terminus, a central proline- and glycine-rich region (CH1, collagen-homologous region 1), and a phosphotyrosine-binding domain. p66Shc contains the sequences for the p52 and p46 isoforms and has an additional amino-terminal proline-rich region (CH2). Serine phosphorylation of the CH2 region has been implicated in apoptotic signaling pathways activated by oxidative stressors.
||p66Shc-/- mice live ~30% longer than their wild-type counterparts and demonstrate an increased resistance to paraquat (a reagent used to induce oxidative stress). There are no other phenotypical or histological differences noted in homozygous p66Shc knockout mice. p66Shc expression is restricted to epithelial cells, whereas p46Shc and p52Shc expression are found in every cell type. Disruptions in the CH1 region of the shc gene, which is shared by all three isoforms, are embryonic-lethal.
|Corresponding human phenotype
||There are no known human conditions that have been associated with an SHC1 allelic variant. One study identified a Met300-to-Val substitution in the shc loci by examining 70 patients with diabetes mellitus. However, a follow-up study based on these data found no significant difference in the allelic frequency of the SHC1 variant in diabetic patients versus control subjects.
||E. Migliaccio, M. Giorgio, S. Mele, G. Pelicci, P. Reboldi, P. P. Pandolfi, L. Lanfrancone, P. G. Pelicci, The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402, 309-313 (1999).
||Not commercially available. Please contact:
Pier Giuseppe Pelicci
Department of Experimental Oncology
Instituto Europeo di Onccologia (IEO)
Via Ripamonti 435
20141 Milan, Italy
||These are two other mice in which the Shc1 gene has been altered in some fashion:
1. Allele: Shc1tm1Paw
Type of change: 2.0 kb of sequence, including exons 2 and 3, were deleted by the insertion of a neomycin selection cassette. The deleted region contained the start codons for the three known isoforms and encoded portions of the PTB domain in each. Although the transcript was undetected in homozygous mutant mice, a truncated protein (40 kD) was identified by Western blot analysis of total embryonic RNA. Reverse transcription polymerase chain reaction and in vitro transcription/translation analysis showed aberrant splicing involving the neo transgene and the initiation of translation to be at codon 134.
Reference: K. M. Lai, T. Pawson, The ShcA phosphotyrosine docking protein sensitizes cardiovascular signaling in the mouse embryo. Genes Dev. 14, 1132-1145 (2000).
2. Allele: Shc1tm1Ravi
Type of change: Exons 1 and 2, which encode the transcriptional start site and the amino terminal region of the three known isoforms, were flanked by a single upstream loxP site and a floxed neo cassette inserted into intron 2. Transient transfection of embryonic stem cells resulted in the excision of the floxed neo cassette, leaving the first two exons surrounded by single loxP sites.
Reference: L. Zhang, V. Camerini, T. P. Bender, K. S. Ravichandran, A nonredundant role for the adapter protein Shc in thymic T cell development. Nat. Immunol. 3, 749-755 (2002).
||Related transgenic/knockout mice:
Copper, zinc superoxide dismutase mice:
Harlequin (Hq) mice:
Manganese superoxide dismutase (Mn SOD or Sod2) mice:
SAGE KE's Genes/Interventions database:
||Oxidative stress, Src homology domain, phosphotyrosine-binding domain
February 26, 2003
- K. M. Lai, T. Pawson, The ShcA phosphotyrosine docking protein sensitizes cardiovascular signaling in the mouse embryo. Genes Dev. 14, 1132-1145 (2000).[Abstract/Free Full Text]
- L. Luzi, S. Confalonieri, P. P. Di Fiore, P. G. Pelicci, Evolution of shc functions from nematode to human. Curr. Opin. Genet. Dev. 10, 668-674 (2000).[CrossRef][Medline]
- S. Nemoto, T. Finkel, Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295, 2450-2452 (2002).[Abstract/Free Full Text]
- H. Tran, A. Brunet, J. M. Grenier, S. R. Datta, A. J. Fornace, P. S. DiStefano, L. W. Chiang, M. E. Greenberg, DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 296, 530-534 (2002).[Abstract/Free Full Text]
- L. Zhang, V. Camerini, T. P. Bender, K. S. Ravichandran, A nonredundant role for the adapter protein Shc in thymic T cell development. Nat. Immunol. 3, 749-755 (2002).[Medline]
Mice). Science's SAGE KE
(26 February 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/8/tg4