Fas gene

APOPTOSIS, PART II THE ROLE OF MUTATED Fas GENES IN TUMORIGENESIS... 

Fas Gene and Its Two Main Transcripts Encoding Membrane and Soluble Isoforms... Ill... 

These finding require further investigation to determine the relationship between tumor biology and defects of Fas-mediated apoptosis. Indeed, Fas gene mutations were first reported in Ipr and mice (A2, L5, W1) and were recently reported in... 

Fig. 1. Fas gene structure containing nine exons corresponding to the three domains EC, TM, and IC, and the main two alternatively spliced transcripts of full-length Fas mRNA and ATM mRNA, which are translated into membrane (mFas) and soluble (sFas) isoforms, respectively.

If Fas gene mutations are significant in tumor biology, mutations may be clustered in the most important region of the gene. Accordingly, the hot spot of the mutations in cancers and the relationship between the mutation domain and the functional impairment are discussed in this section. 

The decoy function of aberrant and intact sFas was discussed above now we will review the attenuating mechanism of aberrant mFas for Fas-mediated apoptosis. Data from our ATL studies and the literature indicate several different mechanisms for attenuating Fas-mediated signaling depending on the aberrant structure of the Fas molecule produced by the mutated Fas gene, as shown in Fig. 8. 

Fig. 7. The distribution of Fas gene mutations within the coding region. The codon number indicated on the x-axis corresponds to the lower horizontal boxes, which indicate the exon numbers of the Fas gene. Mutations are obviously concentrated in exons 6 and 9, which encode the transmembrane domain and the intracytoplasmic region containing the death-signaling domain, respectively. No mutations have been reported in exons 1 or 5. The numbers on top of the bars (162, 234, 244, 251, and 253) show codons that are mutated at high frequency.

B6. Bertoni, R, Conconi, A., Lutrdnari, S., Realini, C., Roggero, E., Baldini, L., Carobbio, S., Cavalli, R, Neri, A., and Zucca, E., Lack of CD95/FAS gene somatic mutations in extranodal, nodal and splenic marginal zone B cell lymphomas. Leukemia 14, 446-448 (2000). 

Zhang, B., Prendergast, G.C., and Fenton, R.G. (2002). Farnesyltransferase inhibitors reverse Ras-mediated inhibition of Fas gene expression. Cancer Res 62 450-458. 

Mutations in the FAS gene Impaired selftolerance by preventing the elimination of activated peripheral T cells Autoimmune lymphoprolifera-tive syndrome (ALPS) type la... 

Fas gene mutations (a) lupus-prone mice b) ALPS (see Table 1), SLE (very rare)... 

Autoimmune lymphoproliferative syndrome (ALPS). Also known as Canale-Smith syndrome. Characterized by lymphadenop-athy, hepatosplenomegaly, autoimmune cytopenias, and hyper-gammaglobulinaemia. Associated with defects in the Fas-FasL apoptosis signalling pathway due to mutations in the Fas gene, the FasL gene, or other genes coding for factors of this pathway. 

Drappa J, Vaishnaw AK, Sullivan KA, Chu JL, Elkon KB (1996) Fas gene mutations in the Canale-Smith syndrome, an inherited lymphoproliferative disorder associated with autoimmunity. N Engl J Med, 335 1643-1649. 

Fisher GH, Rosenberg FJ, Straus SE, Dale JK, Middleton LA, Lin AY, Strober W, Leonardo MJ, Puck JM (1995) Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell, 81 935-946. 

Ramenghi U, Bonissoni S, Migliaretti G, DeFranco S, Bottarel F, Gambaruto C, DiFranco D, Priori R, Conti F, Dianzani I, Valesini G, Merletti F, Dianzani U (2000) Deficiency of the Fas apoptosis pathway without Fas gene mutations is a familial trait predisposing to development of autoimmune diseases and cancer. Blood, 95 3176-3182. 

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