Disease relevance of SMC3

• The immunohistochemical analysis of colon adenocarcinomas from clinical specimens revealed that beta-catenin and SMC3 antigens co-localize with maximal stain intensity within the transformed areas [1].
• We have found previously that SMC3 expression is elevated in a large fraction of human colon carcinomas [1].
• Mutations in Cohesin Complex Members SMC3 and SMC1A Cause a Mild Variant of Cornelia de Lange Syndrome with Predominant Mental Retardation [2].
• Deletion of one or both BMH genes caused hypersensitivity to rapamycin in a manner that was dependent on gene dosage [3].
• HCAP protein was detected in 9 of 14 CaP metastases but not in normal prostate tissues from cadaveric donors or patients with organ-confined tumors [4].

Psychiatry related information on SMC3

• Our data indicate that SMC3 and SMC1A mutations (1) contribute to ~5% of cases of CdLS, (2) result in a consistently mild phenotype with absence of major structural anomalies typically associated with CdLS, and (3) in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation [2].

High impact information on SMC3

• Structural maintenance of chromosomes (SMC) proteins (SMC1, SMC3) are evolutionarily conserved chromosomal proteins that are components of the cohesin complex, necessary for sister chromatid cohesion [5].
• We have previously proposed a similar stabilizing role for bamacan in the basement membrane matrix [6].
• Structural analysis of the mutant SMC3 and SMC1A proteins indicate that all are likely to produce functional cohesin complexes, but we posit that they may alter their chromosome binding dynamics [2].
• SMC1beta is specifically expressed in testes and coimmunoprecipitates with SMC3 from testis nuclear extracts, but not from a variety of somatic cells [7].
• RESULTS: Characterization of cohesin's ATPase activity suggests that hydrolysis depends on the binding of ATP to both Smc1 and Smc3 heads [8].

Biological context of SMC3

• Mass spectrometric analysis of proteins that were immunoprecipitated from the retinal axoneme-enriched fraction using an anti-ORF15 antibody identified two chromosome-associated proteins, structural maintenance of chromosomes (SMC) 1 and SMC3 [9].
• We found that a second complex, hSMC1/hSMC3, is required for metaphase progression in mitotic cells [10].
• The cohesin multiprotein complex containing SMC1, SMC3, Scc3 (SA), and Scc1 (Rad21) is required for sister chromatid cohesion in eukaryotes [11].
• The amino acid sequences of the long, anti-parallel coiled coils of the cohesin subunits SMC1 and SMC3 are almost totally conserved in mammals [12].
• In contrast, mutations predicted to prevent hydrolysis of ATP bound to either head abolished cohesin's association with chromatin but not Scc1's ability to connect Smc1's head with that of Smc3 [13].

Anatomical context of SMC3

• Both SMC1 and SMC3 localized to the cilia of retinal photoreceptors and Madin-Darby canine kidney cells, suggesting a broader physiological relevance of this interaction [9].
• To assess the role of this protein in tumorigenesis, we investigated whether induced overexpression of bamacan/SMC3 could transform normal fibroblasts [14].
• Bamacan is differentially expressed in mouse tissues with the highest levels in testes and brain [15].
• SMC1alpha and SMC3 were also found to localize along meiotic chromosome cores of Spo11 null spermatocytes, in which double-strand break formation required for DNA recombination and homologous pairing were disrupted [16].
• HCAP mRNA was detected in CaP cell lines, in primary CaP tissues and in its osseous metastases [4].

Associations of SMC3 with chemical compounds

• It is also present extracellularly in the form of a chondroitin sulfate proteoglycan known as bamacan [1].
• Perlecan and basement membrane-chondroitin sulfate proteoglycan (bamacan) are two basement membrane chondroitin/dermatan sulfate proteoglycans in the Engelbreth-Holm-Swarm tumor matrix [17].
• Nine patients, all of whom received combination chemotherapy with hexamethylmelamine, cyclophosphamide, doxorubicin, and cisplatin (HCAP), were evaluable for response [18].
• Of these patients, 89 received monthly treatment with CP [cyclophosphamide (1 g/m2) plus cisplatin (60 mg/m2)] and 92 received monthly treatment with HCAP [hexamethylmelamine (150 mg/m2/day X 7), cyclophosphamide (400 mg/m2), doxorubicin (30 mg/m2), and cisplatin (60 mg/m2)] [19].

Physical interactions of SMC3

• SMAP was extracted as a ternary complex with HCAP and KIF3B from the nuclear fraction in the presence of Mg-ATP [20].

Other interactions of SMC3

• We isolated here a SMAP-interacting protein from a human brain cDNA library, identified it to be a human homolog of Xenopus XCAP-E (Xenopus chromosome-associated polypeptide), a subunit of condensins that regulate the assembly and structural maintenance of mitotic chromosomes, and named it HCAP (Human chromosome-associated polypeptide) [20].
• Tissue and subcellular distribution analyses indicated that HCAP was ubiquitously expressed and highly concentrated in the nuclear fraction, where SMAP and KIF3B were also present [20].
• In preretinal membranes, perlecan, bamacan, and Types VI, VIII, XII, and XIV collagen were newly identified [21].

Analytical, diagnostic and therapeutic context of SMC3

• Fusion protein antibodies stained basement membranes in a pattern commensurate with bamacan, and they also Western blotted bamacan core protein from rat L2 cell cultures [6].
• Hinderin/SMC3 complexes could be recovered by immunoprecipitation from cell lysates using an anti-SMC3 antibody, thus demonstrating that the two proteins interact in vivo [22].
• Expression of the human cachexia-associated protein (HCAP) in prostate cancer and in a prostate cancer animal model of cachexia [4].
• Our Western blot analysis revealed that HCAP was present in 9 of 19 urine specimens from cachectic CaP patients but not in 19 urine samples of noncachectic patients [4].
• HCAP mRNA and protein were also detected in LuCaP 35 and PC-3M xenografts from our cachectic animal models [4].

References