Apoptosis is an essential processes required for normal development and homeostasis of all metazoan organisms. Second Mitochondria-Derived Activator of Caspases (Smac) or Direct IAP Binding Protein with low isoelectric point, pI (Diablo) is a proapoptogenic mitochondrial protein that is released to the cytosol in response to diverse apoptotic stimuli, including commonly used chemotherapeutic drugs. The current knowlege about structure and function of Smac/Diablo during programmed cell death, both in mitochondrial and receptor pathways are presented. It has been shown that Diablo mainly interacts with IAPs in the cytochrome c/Apaf-1/caspase-9 pathway, and promotes apoptosis. Diablo is released from the mitochondria into the cytosol occurring downstream of cytochrome c release in response to apoptotic stimuli such as irradiation, DNA damage or cytotoxic drugs. In the cytosol, Smac/Diablo interacts and antagonizes inhibitors of apoptosis proteins (IAPs), thus allowing the activation of caspases and apoptosis. This activity has prompted the synthesis of peptidomimetics that could potentially be used in cancer therapy. The role of Smac/DIABLO in colorectal carcinogenesis is ill defined. Data continues to accumulate to suggest that decreased levels of Smac/DIABLO may be important in chemoradiation-resistance to apoptosis in advanced colon cancer.
Mothers against decapentaplegic homolog 3(SMAD3) is a cytoplasm protein which belongs to the dwarfin/SMAD family. Smad proteins undergo rapid nuclear translocation upon stimulation by transforming growth factor and in so doing transduce the signal into the nucleus. Receptor-regulated SMAD is an intracellular signal transducer and transcriptional modulator activated by TGF-beta and activin type 1 receptor kinases. SMAD3 binds the TRE element in the promoter region of many genes that are regulated by TGF-beta and, on formation of the SMAD3/SMAD4 complex, activates transcription. It also can form a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. SMAD3 has an inhibitory effect on wound healing probably by modulating both growth and migration of primary keratinocytes and by altering the TGF-mediated chemotaxis of monocytes. This effect on wound healing appears to be hormone-sensitive.
SMAD Family Member 4 (SMAD4) is a cytoplasmic protein that belongs to the Dwarfin/SMAD family. SMAD4 contains one MH1 (MAD homology 1) domain and one MH2 (MAD homology 2) domain. It is the component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling. SMAD4 promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. SMAD4 may act as a tumor suppressor. It positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. Mutations or deletions in SMAD4 have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome.
SPARC-related modular calcium-binding protein 1, also known as secreted modular calcium-binding protein 1 and SMOC1, is a member of the SPARC family. SMOC1 is widely expressed in many tissues with a strongest signal in ovary. It contains twoEF-hand domains, oneKazal-like domain and twothyroglobulin type-1 domains. Extracellular matrix proteins have been implicated in the regulation of osteoblast differentiation of bone marrow derived mesenchymal stem cells (BMSCs) through paracrine or autocrine mechanisms. SMOC1 is a regulator of osteoblast differentiation of BMSCs. SMOC1 is highly expressed and secreted in BMSCs stimulated with osteogenic medium (OSM). SMOC1 and SMOC2 are matricellular proteins thought to influence growth factor signaling, migration, proliferation, and angiogenesis. SMOC1 and SMOC2 may mediate intercellular signaling and cell type-specific differentiation during gonad and reproductive tract development.
SMOC-2 (secreted, or SPARC-related, modular calcium-binding protein 2), previously called SMAP2 (smooth muscle-associated protein 2), is a 55 kDa glycoprotein that is a member of the SPARC family of matricellular proteins. The human SMOC-2 cDNA encodes 446 amino acids (aa), including a 21 aa signal sequence, a Kazal-like domain (aa 40-84), two thyroglobulin type-1 segments (aa 87-153 and 213-281) and two EF-hand sequences (aa 347-382 and 384-419). Of three splice variants, one shows a 13 aa substitution for aa 442-446, another shows an 11 aa insertion after Thr170, and a third contains both of these variations. SMOC-2 is widely expressed in the extracellular matrix and appears to have adhesion-related functions. Recombinant bacterially produced human SMOC-1 and SMOC-2 can bind the acute phase protein, C-reactive protein, and the adhesion proteins, fibulin and vitronectin, while keratinocyte SMOC-2 binds integrins alpha v beta 1 and alpha v beta 6. SMOC-2 promotes cell cycle progression by signaling through the integrin-linked kinase (ILK) to upregulate cyclin-D1. When expressed in the endothelial extracellular matrix, it potentiates growth factor-induced angiogenesis. SMOC-2 expression is upregulated during neointima formation, promoting proliferation and migration of vascular smooth muscle. In the skin, it promotes keratinocyte attachment and migration. Since Kazal and thyroglobulin domains are often found in protease inhibitors, SMOC-2 is also proposed to inhibit proteases in the lung and artery.
Sphingomyelin phosphodiesterase 1 (SMPD1) , also known as ASM ( acid sphingomyelinase ), is a member of the acid sphingomyelinase family of enzymes. Three isoforms have been identified, isoform 1 is 631 amino acids (aa) in length as the pro form, while Isoform 2 and isoform 3 have lost catalytic activity. The active SMPD1 isoform 1 contains one saposin B-type domain that likely interacts with sphingomyelin, and a catalytic region. Human SMPD1 is 86% aa identical to mouse SMPD1. SMPD1 is a monomeric lysosomal enzyme that converts sphingomyelin (a plasma membrane lipid ) into ceramide through the removal of phosphorylcholine. This generates second messenger components that participate in signal transduction. Defects in SMPD1 are the cause of Niemann-Pick disease type A (NPA) and type B (NPB), also known as Niemann-Pick disease classical infantile form and Niemann-Pick disease visceral form. Niemann-Pick disease is a clinically and genetically heterogeneous recessive disorder. NPB has little if any neurologic involvement and patients may survive into adulthood.
Acid sphingomyelinase-like phosphodiesterase 3a (SMPDL3A ) is a novel liver X receptor (LXR) -regulated gene; with an LXR response element within its promoter. The induction of SMPDL3A is LXR-dependent and is restricted to human blood cells with no induction observed in mouse cellular systems. LXR function as physiological sensors of cholesterol metabolites (oxysterols); regulating key genes involved in cholesterol and lipid metabolism. LXRs have been extensively studied in both human and rodent cell systems; revealing their potential therapeutic value in the contexts of atherosclerosis and inflammatory diseases.
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