Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Abstract

Charcot–Marie–Tooth neuropathy type 1C (CMT1C) is an autosomal dominant demyelinating peripheral neuropathy caused by missense mutations in the small integral membrane protein of lysosome/late endosome (SIMPLE) gene. To investigate the prevalence of SIMPLE mutations, we screened a cohort of 152 probands with various types of demyelinating or axonal and pure motor or sensory inherited neuropathies. SIMPLE mutations were found only in CMT1 patients, including one G112S and one W116G missense mutations. A novel I74I polymorphism was identified, yet no splicing defect of SIMPLE is likely. Haplotype analysis of STR markers and intragenic SNPs linked to the gene demonstrated that families with the same mutation are unlikely to be related. The clustering of the G112S, T115N, and W116G mutations within five amino acids suggests this domain may be critical to peripheral nerve myelination. Electrophysiological studies showed that CMT1C patients from six pedigrees (n = 38) had reduced nerve conduction velocities ranging from 7.5 to 27.0m/sec (peroneal). Two patients had temporal dispersion of nerve conduction and irregularity of conduction slowing, which is unusual for CMT1 patients. We report the expression of SIMPLE in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in CMT1C.

Annexin II binds progastrin and gastrin-like peptides, and mediates growth factor effects of autocrine and exogenous gastrins on colon cancer and intestinal epithelial cells

“…The overexpressing S 7 clones (Figure 9e), demonstrated an enhanced response to FCS, especially at higher concentrations. The relative levels of PG in the cellular lysates of the cells (measured as described previously, Cobb et al, 2004) were similar in the S 7 , AS 2 and AS 3 clones, compared to that in the C cells (Supplementary Table 3), and increased similarly in all the S, AS and C clones, in a dose-dependent manner, in response to FCS, as published previously (Singh et al, 1996); these results suggest that endogenous ANX II likely plays an important role in mediating growth factor effects of autocrine PG. Table 1.…”

“…PG and GG exert cocarcinogenic effects on colon carcinogenesis in response to azoxymethane (Singh et al, 2000a, b;Aly et al, 2001;Cobb et al, 2004). Elevated levels of circulating PG are measured in hypergastrinemia owing to various etiologies (including ZE syndrome and pernicious anemia) (Rengifo-Cam and Singh, 2004), and in patients with colorectal cancer (CRC) (Siddheshwar et al, 2001).…”

“…Elevated levels of circulating PG are measured in hypergastrinemia owing to various etiologies (including ZE syndrome and pernicious anemia) (Rengifo-Cam and Singh, 2004), and in patients with colorectal cancer (CRC) (Siddheshwar et al, 2001). As potent co-carcinogenic effects of PG are reported in Fabp-PG mice, that express 'patho-physiological' concentrations of hPG (0.1-5 nM) (Cobb et al, 2004), it suggests that elevated levels of circulating PG, as measured in patients with hyperastrinemia and CRC, may play a role in colon carcinogenesis.…”

“…Immunoprecipitation and WB analysis Cellular lysates were prepared from cells in culture as described previously (Singh et al, 1994b;Wu et al, 2000Wu et al, , 2003Cobb et al, 2004). Specific Abs generated against rhPG in our laboratory were used (Cobb et al, 2004).…”

“…Specific Abs generated against rhPG in our laboratory were used (Cobb et al, 2004). Mouse monoclonal Abs against ANX II (BD Biosciences, Pharmingen, San Diego, CA, USA) and/or anti-ANX II polyclonal Abs (Santa Cruz, Santa Cruz, CA, USA) were used as per the recommendation of the companies.…”