Disease relevance of Mtss1

• Missing in metastasis (MIM) gene encodes an actin binding protein that is expressed at low levels in a subset of malignant cell lines [1].
• Spondylocostal dysostosis (SD, MIM 277300) is a group of vertebral malsegmentation syndromes with reduced stature resulting from axial skeletal defects [2].
• Keutel syndrome (KS, MIM 245150) is an autosomal recessive disorder characterized by abnormal cartilage calcification, peripheral pulmonary stenosis and midfacial hypoplasia [3].
• Clustered attacks of epileptic episodes originating from the frontal lobe during sleep are the main symptoms of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE, MIM 600513) [4].
• Hirschsprung disease (HSCR, MIM #142623) is a multigenic neurocristopathy (neural crest disorder) characterized by absence of enteric ganglia in a variable portion of the distal colon [5].

Psychiatry related information on Mtss1

• Congenital insensitivity to pain with anhidrosis (CIPA; MIM 256800) is an autosomal-recessive disorder characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating) and absence of reaction to noxious stimuli, self-mutilating behaviour and mental retardation [6].

High impact information on Mtss1

• Mulibrey nanism (for muscle-liver-brain-eye nanism, MUL; MIM 253250) is an autosomal recessive disorder that involves several tissues of mesodermal origin, implying a defect in a highly pleiotropic gene [7].
• Infantile malignant autosomal recessive osteopetrosis (MIM 259700) is a severe bone disease with a fatal outcome, generally within the first decade of life [8].
• Subsets of HSCR individuals also present with neural crest-derived melanocyte deficiencies (Hirschsprung-Waardenburg, HSCR-WS, MIM #277580) [5].
• KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2 [9].
• Together, Gli1 and MIM recapitulate Shh-mediated epidermal proliferation and invasion in regenerated human skin [10].

Chemical compound and disease context of Mtss1

• We postulate that MIM-B may be a regulator of actin assembly downstream of tyrosine kinase signalling and that this activity may explain the involvement of MIM in the metastasis of cancer cells [11].

Biological context of Mtss1

• However, an MIM mutant with deletion of the WH2 domain, which is responsible for G-actin binding, enhanced cell motility [1].
• These data show that MIM is an ATP-G-actin binding protein that regulates cytoskeletal dynamics in specialized mammalian cell-types [12].
• This mouse gene also shows strong sequence homology to human MIM (Missing in Metastasis), a cDNA fragment that is present in non-metastatic but absent in metastatic bladder cancer cell lines [12].
• They further suggest that a melanoma metastasis-suppressor gene(s) is encoded on chromosome 6 or is regulated by genes on chromosome 6 [13].
• To study the molecular and cellular basis of mosaicism, we established a mouse model for the autosomal-dominant skin blistering disorder, epidermolytic hyperkeratosis (MIM 113800), which is caused by mutations in either keratin K1 or K10 [14].

Anatomical context of Mtss1

• Here, we show that endogenous MIM is induced in a patched1-dependent manner and regulates the actin cytoskeleton [15].
• However, the MIM/ATP-G-actin complex can participate in actin filament assembly at the barbed end [12].
• In adult mice, the strongest expression of MIM mRNA is in liver, outer layers of the kidney, and in the Purkinje cells of the brain [12].
• Overexpression of mouse MIM in NIH 3T3 cells results in the disappearance of actin stress fibers and appearance of abnormal actin filament structures [12].
• Northern blot and in situ hybridizations show that MIM is strongly expressed in the developing neurons and skeletal and cardiac muscles in mouse embryos [12].

Associations of Mtss1 with chemical compounds

• In contrast, deletion of an MIM proline-rich domain, which is required for an optimal binding to cortactin, substantiated the MIM-mediated inhibition of cell motility [1].
• Receptor tyrosine phosphatase-dependent cytoskeletal remodeling by the hedgehog-responsive gene MIM/BEG4 [15].
• We generated a knockout mouse model for guanidinoacetate N-methyltransferase (GAMT) deficiency (MIM 601240), the first discovered human creatine deficiency syndrome, by gene targeting in embryonic stem cells [16].
• We report a functional link between expression of the metastasis suppressor gene nm23 and cancer cell sensitivity to the alkylating agent cisplatin [17].
• We previously showed that introduction of a normal, neomycin-tagged human chromosome 11 reduces the metastatic capacity of MDA-MB-435 (435) human breast carcinoma cells by 70-90% without affecting tumorigenicity, suggesting the presence of one or more metastasis suppressor genes encoded on human chromosome 11 [18].

Regulatory relationships of Mtss1

• Involvement of histone deacetylation in ras-induced down-regulation of the metastasis suppressor RECK [19].

Other interactions of Mtss1

• We previously identified Basal cell carcinoma-enriched gene 4 (BEG4)/Missing in Metastasis (MIM), a Shh-inducible, Wiskott-Aldrich homology 2 domain-containing protein that potentiates Gli transcription (Callahan, C.A., T. Ofstad, L. Horng, J.K. Wang, H.H. Zhen, P.A. Coulombe, and A.E. Oro. 2004. Genes Dev. 18:2724-2729) [15].
• DRnm23 belongs to a multigene family which includes nm23-H1, the first bona fide metastasis suppressor gene, nm23-H2, nm23-H4, and nm23-H5 [20].
• Gelsolin functions as a metastasis suppressor in B16-BL6 mouse melanoma cells and requirement of the carboxyl-terminus for its effect [21].
• The nm23-M1, a putative metastasis-suppressor gene, and its homologs are involved in development and differentiation [22].

Analytical, diagnostic and therapeutic context of Mtss1

• Site-directed mutagenesis demonstrates that the actin monomer-binding site resides in the C-terminal WH2 domain of MIM [12].
• A PCR analysis of various microcell hybrid clones with sequence-tagged site markers indicates that the metastasis suppressor activity is located in the q24.2 region of chromosome 16 [23].
• Intrasplenic transplantation of GFP-expressing parental MIM cells into Fas-injured livers of SCID mice revealed liver-reconstituting activity [24].
• The use of these models has enabled preclinical chemotherapeutic, chemoprevention, and genetic therapy studies in vivo, the testing of gene delivery systems, and the identification of tumour and metastasis suppressor and inducer genes [25].
• CONCLUSIONS: Animal models of metastasis have supported drug development and have been useful for identification of metastasis suppressor and promoter genes as novel targets for the development of novel therapies [26].

References