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Xpc  -  xeroderma pigmentosum, complementation...

Mus musculus

Synonyms: DNA repair protein complementing XP-C cells homolog, Xeroderma pigmentosum group C-complementing protein homolog, p125
 
 
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Disease relevance of Xpc

  • Functional TCR of DMBA adducts in Xpc(-/-) mice thus appears to alleviate DMBA toxicity [1].
  • As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome [2].
  • We previously developed a mouse model of skin cancer with mutations in the xeroderma pigmentosum group C gene (Xpc) [3].
  • Skin tumors from Xpc-/- mice were exclusively well or moderately well-differentiated squamous cell carcinomas [4].
  • We investigated the impact of deficiencies in NER subpathways on apoptosis, hyperplasia, and cell cycle progression in the epidermis of UVB-exposed CS group B (Csb(-/-)) mice (no TCR), XP group C (Xpc(-/-)) mice (no GGR), and XP group A (Xpa(-/-)) mice (no TCR and no GGR) [5].
 

High impact information on Xpc

  • A subset of animals heterozygous for Csb and Xpc deficiencies was more mildly affected, demonstrating ataxia and Purkinje cell loss at 3 months of age [6].
  • Mouse, Csb(-/-), and Xpc(-/-) embryonic fibroblasts each exhibited increased sensitivity to UV light, which generates bulky DNA damage that is a substrate for excision repair [6].
  • Flow cytometric analyses of single-cell suspensions from UV-exposed Xpc(-/-) epidermis further showed that the "near-4N" arrested cells retained cytokeratin 5 and lacked cytokeratin 10 [7].
  • In vivo BrdUrd pulse-chase labeling (>17 h after UV exposure) showed that DNA replication after UV exposure was resumed in Xpc(-/-) mice, but it did not reveal any evidence of retained BrdUrd-labeled S-phase cells in the basal layer of the epidermis at 72 h [7].
  • In Xpc(-/-) mice deficient in global genome nucleotide excision repair (GGR), a cell-cycle arrest of epidermal cells in late S-phase [with near-double normal diploid (4N) DNA content] was observed 48-72 h after UV exposure [7].
 

Chemical compound and disease context of Xpc

 

Biological context of Xpc

  • However, the mutagenic response in Xpc(-/-) mice was +/- 2-fold enhanced at both the Hprt and the Aprt gene compared to heterozygous controls, indicating that GGR at least partially removes DMBA adducts from the genome overall [1].
  • We have generated mouse strains defective in the Xpc gene, which is required for nucleotide excision repair (NER) of DNA [9].
  • The induction kinetics of the patches in Xpc-deficient mice differed notably from the others: there was a stationary phase (days 13-41) where the numbers were limited to 5-10 patches per mouse before an explosive increase which ran parallel to the other groups [10].
  • Subsequently Xpa and Xpc knockouts have proved to be good models for the human NER deficiency disease, xeroderma pigmentosum, leading to speculation that the recombination, rather than the NER deficit is the key to the Ercc1 knockout phenotype [11].
  • Age-dependent spontaneous mutagenesis in Xpc mice defective in nucleotide excision repair [12].
 

Anatomical context of Xpc

  • DMBA-induced SCE frequencies in mouse dermal fibroblasts were significantly enhanced in Xpa- and Csb-, but not in Xpc-deficient background compared to the frequency in normal fibroblasts [1].
  • Here, we show that spontaneous mutant frequencies at the Hprt gene increased 30-fold in T-lymphocytes of 1 year old Xpc-/- mice, possessing only functional transcription-coupled repair (TCR) [12].
  • Analysis of calyculin A (CA)-induced premature chromosome condensation (PCC) of cultured Xpc(-/-) keratinocytes showed that the delayed arrest occurred in late S phase rather than in G(2)-phase [13].
  • Double occupancy by antigen and p55 or p125, however, renders Ia-compatible, but not Ia-incompatible, resting B cells susceptible to stimulation [14].
  • Using PECAM-1-deficient mice, we show that the platelets have impaired "outside-in" integrin alpha(IIb)beta3 signaling with impaired platelet spreading on fibrinogen, failure to retract fibrin clots in vitro, and reduced tyrosine phosphorylation of focal adhesion kinase p125 (125FAK) following integrin alpha(IIb)beta3-mediated platelet aggregation [15].
 

Associations of Xpc with chemical compounds

 

Regulatory relationships of Xpc

 

Other interactions of Xpc

  • We also show that Xpc Trp53 double heterozygous mutants are more predisposed to skin cancer than Trp53 single heterozygous mice [4].
  • We also documented previously increased predisposition to UV radiation-induced skin cancers in Xpc-/- Apex+/- mice [4].
  • Csb(-/-) mice that are also deficient in global genomic repair [Csb(-/-)/xeroderma pigmentosum C (Xpc)(-/-)] are more profoundly affected, exhibiting whole-body wasting, ataxia, and neural loss by postnatal day 21 [6].
 

Analytical, diagnostic and therapeutic context of Xpc

  • Surprisingly, while all intraperitoneally-treated Xpc(-/-) mice survived a dose of 40 mg/kg DMBA, a substantial fraction of the treated Xpa(-/-) and Csb(-/-) mice died a few days after treatment with a 20-fold lower dose [1].

References

  1. DMBA-induced toxic and mutagenic responses vary dramatically between NER-deficient Xpa, Xpc and Csb mice. Wijnhoven, S.W., Kool, H.J., Mullenders, L.H., Slater, R., van Zeeland, A.A., Vrieling, H. Carcinogenesis (2001) [Pubmed]
  2. Tissue specific mutagenic and carcinogenic responses in NER defective mouse models. Wijnhoven, S.W., Hoogervorst, E.M., de Waard, H., van der Horst, G.T., van Steeg, H. Mutat. Res. (2007) [Pubmed]
  3. Mutations in the Trp53 gene of UV-irradiated Xpc mutant mice suggest a novel Xpc-dependent DNA repair process. Nahari, D., McDaniel, L.D., Task, L.B., Daniel, R.L., Velasco-Miguel, S., Friedberg, E.C. DNA Repair (Amst.) (2004) [Pubmed]
  4. Ultraviolet B radiation-induced skin cancer in mice defective in the Xpc, Trp53, and Apex (HAP1) genes: genotype-specific effects on cancer predisposition and pathology of tumors. Cheo, D.L., Meira, L.B., Burns, D.K., Reis, A.M., Issac, T., Friedberg, E.C. Cancer Res. (2000) [Pubmed]
  5. Differential role of transcription-coupled repair in UVB-induced G2 arrest and apoptosis in mouse epidermis. van Oosten, M., Rebel, H., Friedberg, E.C., van Steeg, H., van der Horst, G.T., van Kranen, H.J., Westerman, A., van Zeeland, A.A., Mullenders, L.H., de Gruijl, F.R. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  6. Increased apoptosis, p53 up-regulation, and cerebellar neuronal degeneration in repair-deficient Cockayne syndrome mice. Laposa, R.R., Huang, E.J., Cleaver, J.E. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  7. Epidermal transit of replication-arrested, undifferentiated keratinocytes in UV-exposed XPC mice: an alternative to in situ apoptosis. Stout, G.J., Westdijk, D., Calkhoven, D.M., Pijper, O., Backendorf, C.M., Willemze, R., Mullenders, L.H., de Gruijl, F.R. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. Cancer predisposition in mutant mice defective in multiple genetic pathways: uncovering important genetic interactions. Meira, L.B., Reis, A.M., Cheo, D.L., Nahari, D., Burns, D.K., Friedberg, E.C. Mutat. Res. (2001) [Pubmed]
  9. Defective nucleotide excision repair in xpc mutant mice and its association with cancer predisposition. Friedberg, E.C., Bond, J.P., Burns, D.K., Cheo, D.L., Greenblatt, M.S., Meira, L.B., Nahari, D., Reis, A.M. Mutat. Res. (2000) [Pubmed]
  10. Relationship between UV-induced mutant p53 patches and skin tumours, analysed by mutation spectra and by induction kinetics in various DNA-repair-deficient mice. Rebel, H., Kram, N., Westerman, A., Banus, S., van Kranen, H.J., de Gruijl, F.R. Carcinogenesis (2005) [Pubmed]
  11. DNA repair gene Ercc1 is essential for normal spermatogenesis and oogenesis and for functional integrity of germ cell DNA in the mouse. Hsia, K.T., Millar, M.R., King, S., Selfridge, J., Redhead, N.J., Melton, D.W., Saunders, P.T. Development (2003) [Pubmed]
  12. Age-dependent spontaneous mutagenesis in Xpc mice defective in nucleotide excision repair. Wijnhoven, S.W., Kool, H.J., Mullenders, L.H., van Zeeland, A.A., Friedberg, E.C., van der Horst, G.T., van Steeg, H., Vrieling, H. Oncogene (2000) [Pubmed]
  13. Mismatch repair protein Msh2 contributes to UVB-induced cell cycle arrest in epidermal and cultured mouse keratinocytes. van Oosten, M., Stout, G.J., Backendorf, C., Rebel, H., de Wind, N., Darroudi, F., van Kranen, H.J., de Gruijl, F.R., Mullenders, L.H. DNA Repair (Amst.) (2005) [Pubmed]
  14. T cell-dependent activation of resting B cells: requirement for both nonspecific unrestricted and antigen-specific Ia-restricted soluble factors. Anderson, J., Melchers, F. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  15. The Ig-ITIM superfamily member PECAM-1 regulates the "outside-in" signaling properties of integrin alpha(IIb)beta3 in platelets. Wee, J.L., Jackson, D.E. Blood (2005) [Pubmed]
  16. 2-AAF-induced tumor development in nucleotide excision repair-deficient mice is associated with a defect in global genome repair but not with transcription coupled repair. Hoogervorst, E.M., van Oostrom, C.T., Beems, R.B., van Benthem, J., van den Berg, J., van Kreijl, C.F., Vos, J.G., de Vries, A., van Steeg, H. DNA Repair (Amst.) (2005) [Pubmed]
  17. 3,4-Epoxy-1-butene, a reactive metabolite of 1,3-butadiene, induces somatic mutations in Xpc-null mice. Wickliffe, J.K., Galbert, L.A., Ammenheuser, M.M., Herring, S.M., Xie, J., Masters, O.E., Friedberg, E.C., Lloyd, R.S., Ward, J.B. Environ. Mol. Mutagen. (2006) [Pubmed]
  18. Focal adhesion-associated proteins p125FAK and paxillin are substrates for bradykinin-stimulated tyrosine phosphorylation in Swiss 3T3 cells. Leeb-Lundberg, L.M., Song, X.H., Mathis, S.A. J. Biol. Chem. (1994) [Pubmed]
  19. Dissociation of mitogen-activated protein kinase activation from p125 focal adhesion kinase tyrosine phosphorylation in Swiss 3T3 cells stimulated by bombesin, lysophosphatidic acid, and platelet-derived growth factor. Seufferlein, T., Withers, D.J., Mann, D., Rozengurt, E. Mol. Biol. Cell (1996) [Pubmed]
  20. Prostaglandin F2 alpha enhances tyrosine phosphorylation and DNA synthesis through phospholipase C-coupled receptor via Ca(2+)-dependent intracellular pathway in NIH-3T3 cells. Watanabe, T., Nakao, A., Emerling, D., Hashimoto, Y., Tsukamoto, K., Horie, Y., Kinoshita, M., Kurokawa, K. J. Biol. Chem. (1994) [Pubmed]
  21. Genotype-specific Trp53 mutational analysis in ultraviolet B radiation-induced skin cancers in Xpc and Xpc Trp53 mutant mice. Reis, A.M., Cheo, D.L., Meira, L.B., Greenblatt, M.S., Bond, J.P., Nahari, D., Friedberg, E.C. Cancer Res. (2000) [Pubmed]
 
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