SKI protein
Encyclopedia
The Ski protein is a nuclear protooncoprotein
that is associated with tumors at high cellular concentrations. Ski has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes
inside the nucleus of the cell as well as disrupting signaling proteins that activate genes.
Ski negatively regulates transforming growth factor-beta (TGF-beta) by directly interacting with Smads
and repressing the transcription of TGF-beta responsive genes. This has been associated with cancer due to the large number of roles that peptide growth factors, of which TGF-beta are a subfamily, play in regulating cellular functions such as cell proliferation, apoptosis
, specification, and developmental fate
.
The name Ski comes from the Sloan-Kettering Institute where the protein was initially discovered.
tumor suppressor gene at the locus 1p36.3 locus of a gene, suggesting a similar function to the p73 gene.
The SKI protein has a 728 amino acid
sequence, with multiple domain
s and is expressed both inside and outside of the nucleus. It is in the same family as the SnoN
protein. The different domains have different functions, with the primary domains interacting with Smad proteins. The protein has a helix-turn-helix
motif
, a cysteine
and histidine
rich area which gives rise to the zinc finger
motif, a basic amino acid region, and leucine zipper
. All these domains, including a proline
rich region, are consistent with the fact that the protein must have domains that allow it to interact with other proteins. The protein also has hydrophobic regions which come into contact with Smad proteins rich in leucine
and phenylalanine
amino acid regions. Recent studies have suggested a domain similar to the Dachshund protein. The SKI-Dachshund homology domain (SKI-DHD) contains the helix turn helix domains of the protein and the beta-alpha-beta turn motifs.
s depend on the SKI protein as a transcription co-regulator inducing transformation. The aforementioned DHD region is specifically employed for protein-protein interactions, while the 191 amino acid C terminus mediates oligomerization. Recent research shows that the SKI protein in cancerous cells acts as a suppressor, inhibiting transforming growth factor β (TFG- β) signaling
. TFG- β is a protein which regulates cell growth
. Signaling is regulated by a family of proteins called the Smad proteins. SKI is present in all adult and embryonic cells at low levels, however an over expression of the protein is characteristic of tumor cells. It is thought that high levels of SKI protein inactivate tumor suppression by displacement of other proteins and interference with the signaling pathway of TGF- β. The SKI protein and the CPB protein compete for binding with the Smad proteins, specifically competing with the Smad-3
and CReB
-binding protein interactions. SKI also directly interacts with the R-Smad ∙ Smad-4
complex, which directly represses normal transcription of the TGF-β responsive genes, inactivating the cell’s ability to stop growth and division, creating cancerous cells.
SKI has been linked to various cancers including human melanoma
s, esophageal squamous cell carcinoma, cervical cancer
and the process of tumor progression. The link of SKI with human melanoma has been the most studied area of the protein’s link to cancer. Currently it is thought that the SKI protein prevents response to TFG- β levels, causing tumor formation.
protein was identified as a similar protein and is often discussed in conjugation with the Ski protein in publications. Recent research suggests that the role of SnoN could be somewhat different, and could potentially even play an antagonistic role.
Other recent studies have determined Fussel-15 and Fussel-18 to be homologous to the Ski/Sno family of proteins. Fussel-15 has been found to play much the same role as the Ski/Sno proteins, however its expression is not as ubiquitous as the Ski/Sno proteins. Fussel-18 has been found to have an inhibitory role in the TGF-beta signaling.
with SKIL
, NFIX
, SNW1
, MECP2
, HIPK2
, Promyelocytic leukemia protein
, Mothers against decapentaplegic homolog 3
, Mothers against decapentaplegic homolog 1
and Mothers against decapentaplegic homolog 2
.
Oncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
that is associated with tumors at high cellular concentrations. Ski has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
inside the nucleus of the cell as well as disrupting signaling proteins that activate genes.
Ski negatively regulates transforming growth factor-beta (TGF-beta) by directly interacting with Smads
R-SMAD
R-SMAD stands for receptor-regulated SMAD. Smads are transcription factors that transduce extracellular TGF-ß superfamily ligand signaling from cell membrane bound TGF-ß receptors into the nucleus where they activate transcription TGF-ß target genes...
and repressing the transcription of TGF-beta responsive genes. This has been associated with cancer due to the large number of roles that peptide growth factors, of which TGF-beta are a subfamily, play in regulating cellular functions such as cell proliferation, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, specification, and developmental fate
Cell fate determination
Within the field of developmental biology one goal is to understand how a particular cell develops into the final cell type , essentially how a cell’s fate is determined. Within an embryo, 4 processes play out at the cellular and tissue level to essentially create the final organism...
.
The name Ski comes from the Sloan-Kettering Institute where the protein was initially discovered.
Gene
The SKI proto-oncogene is located at a region close to the p73P73
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein...
tumor suppressor gene at the locus 1p36.3 locus of a gene, suggesting a similar function to the p73 gene.
Protein
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence, with multiple domain
Protein domain
A protein domain is a part of protein sequence and structure that can evolve, function, and exist independently of the rest of the protein chain. Each domain forms a compact three-dimensional structure and often can be independently stable and folded. Many proteins consist of several structural...
s and is expressed both inside and outside of the nucleus. It is in the same family as the SnoN
SKIL
Ski-like protein is a protein that in humans is encoded by the SKIL gene.-Interactions:SKIL has been shown to interact with SKI protein, Mothers against decapentaplegic homolog 3 and Mothers against decapentaplegic homolog 2.-Further reading:...
protein. The different domains have different functions, with the primary domains interacting with Smad proteins. The protein has a helix-turn-helix
Helix-turn-helix
In proteins, the helix-turn-helix is a major structural motif capable of binding DNA. It is composed of two α helices joined by a short strand of amino acids and is found in many proteins that regulate gene expression...
motif
Structural motif
In a chain-like biological molecule, such as a protein or nucleic acid, a structural motif is a supersecondary structure, which appears also in a variety of other molecules...
, a cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
and histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
rich area which gives rise to the zinc finger
Zinc finger
Zinc fingers are small protein structural motifs that can coordinate one or more zinc ions to help stabilize their folds. They can be classified into several different structural families and typically function as interaction modules that bind DNA, RNA, proteins, or small molecules...
motif, a basic amino acid region, and leucine zipper
Leucine zipper
A leucine zipper, aka leucine scissors, is a common three-dimensional structural motif in proteins. These motifs are usually found as part of a DNA-binding domain in various transcription factors, and are therefore involved in regulating gene expression...
. All these domains, including a proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
rich region, are consistent with the fact that the protein must have domains that allow it to interact with other proteins. The protein also has hydrophobic regions which come into contact with Smad proteins rich in leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
and phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
amino acid regions. Recent studies have suggested a domain similar to the Dachshund protein. The SKI-Dachshund homology domain (SKI-DHD) contains the helix turn helix domains of the protein and the beta-alpha-beta turn motifs.
Function
The SKI oncogene is present in all cells, and is commonly active during development. Specifically, avian fibroblastFibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s depend on the SKI protein as a transcription co-regulator inducing transformation. The aforementioned DHD region is specifically employed for protein-protein interactions, while the 191 amino acid C terminus mediates oligomerization. Recent research shows that the SKI protein in cancerous cells acts as a suppressor, inhibiting transforming growth factor β (TFG- β) signaling
TGF beta signaling pathway
The Transforming growth factor beta signaling pathway is involved in many cellular processes in both the adult organism and the developing embryo including cell growth, cell differentiation, apoptosis, cellular homeostasis and other cellular functions. In spite of the wide range of cellular...
. TFG- β is a protein which regulates cell growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
. Signaling is regulated by a family of proteins called the Smad proteins. SKI is present in all adult and embryonic cells at low levels, however an over expression of the protein is characteristic of tumor cells. It is thought that high levels of SKI protein inactivate tumor suppression by displacement of other proteins and interference with the signaling pathway of TGF- β. The SKI protein and the CPB protein compete for binding with the Smad proteins, specifically competing with the Smad-3
Mothers against decapentaplegic homolog 3
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene. SMAD3 is a member of the SMAD family of proteins.The human SMAD3 gene is located on chromosome 15...
and CReB
CREB
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
-binding protein interactions. SKI also directly interacts with the R-Smad ∙ Smad-4
Mothers against decapentaplegic homolog 4
SMAD family member 4, also known as SMAD4, is a protein that in humans is encoded by the SMAD4 gene.SMAD4 is a 552-amino acid protein involved in cell signaling. It belongs to the Darfwin family of proteins that modulate members of the TGFβ protein superfamily...
complex, which directly represses normal transcription of the TGF-β responsive genes, inactivating the cell’s ability to stop growth and division, creating cancerous cells.
SKI has been linked to various cancers including human melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
s, esophageal squamous cell carcinoma, cervical cancer
Cervical cancer
Cervical cancer is malignant neoplasm of the cervix uteri or cervical area. One of the most common symptoms is abnormal vaginal bleeding, but in some cases there may be no obvious symptoms until the cancer is in its advanced stages...
and the process of tumor progression. The link of SKI with human melanoma has been the most studied area of the protein’s link to cancer. Currently it is thought that the SKI protein prevents response to TFG- β levels, causing tumor formation.
Related research
Other research has identified proteins similar to Ski. The SnoNSKIL
Ski-like protein is a protein that in humans is encoded by the SKIL gene.-Interactions:SKIL has been shown to interact with SKI protein, Mothers against decapentaplegic homolog 3 and Mothers against decapentaplegic homolog 2.-Further reading:...
protein was identified as a similar protein and is often discussed in conjugation with the Ski protein in publications. Recent research suggests that the role of SnoN could be somewhat different, and could potentially even play an antagonistic role.
Other recent studies have determined Fussel-15 and Fussel-18 to be homologous to the Ski/Sno family of proteins. Fussel-15 has been found to play much the same role as the Ski/Sno proteins, however its expression is not as ubiquitous as the Ski/Sno proteins. Fussel-18 has been found to have an inhibitory role in the TGF-beta signaling.
Interactions
SKI protein has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with SKIL
SKIL
Ski-like protein is a protein that in humans is encoded by the SKIL gene.-Interactions:SKIL has been shown to interact with SKI protein, Mothers against decapentaplegic homolog 3 and Mothers against decapentaplegic homolog 2.-Further reading:...
, NFIX
NFIX
Nuclear factor 1 X-type is a protein that in humans is encoded by the NFIX gene.-Interactions:NFIX has been shown to interact with SKI protein....
, SNW1
SNW1
SNW domain-containing protein 1 is a protein that in humans is encoded by the SNW1 gene.-Interactions:SNW1 has been shown to interact with Histone deacetylase 2, SKI protein, Retinoblastoma protein, PABPN1, CIR, RBPJ, Nuclear receptor coactivator 1, Nuclear receptor co-repressor 2, Calcitriol...
, MECP2
MECP2
MECP2 is a gene that provides instructions for making its protein product, MECP2, also referred to as MeCP2. MECP2 appears to be essential for the normal function of nerve cells. The protein seems to be particularly important for mature nerve cells, where it is present in high levels...
, HIPK2
HIPK2
Homeodomain-interacting protein kinase 2 is an enzyme that in humans is encoded by the HIPK2 gene.-Interactions:HIPK2 has been shown to interact with SKI protein, Death associated protein 6, P53, CREB binding protein, Mothers against decapentaplegic homolog 1, TP53INP1 and RANBP9.-Further reading:...
, Promyelocytic leukemia protein
Promyelocytic leukemia protein
Probable transcription factor PML is a tumor suppressor protein that in humans is encoded by the PML gene.-Interactions:Promyelocytic leukemia protein has been shown to interact with Retinoic acid receptor alpha, HDAC1, Nerve Growth factor IB, SKI protein, Zinc finger and BTB domain-containing...
, Mothers against decapentaplegic homolog 3
Mothers against decapentaplegic homolog 3
Mothers against decapentaplegic homolog 3 also known as SMAD family member 3 or SMAD3 is a protein that in humans is encoded by the SMAD3 gene. SMAD3 is a member of the SMAD family of proteins.The human SMAD3 gene is located on chromosome 15...
, Mothers against decapentaplegic homolog 1
Mothers against decapentaplegic homolog 1
Mothers against decapentaplegic homolog 1 also known as SMAD family member 1 or SMAD1 is a protein that in humans is encoded by the SMAD1 gene.-Nomenclature:...
and Mothers against decapentaplegic homolog 2
Mothers against decapentaplegic homolog 2
Mothers against decapentaplegic homolog 2 also known as SMAD family member 2 or SMAD2 is a protein that in humans is encoded by the SMAD2 gene. MAD homolog 2 belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' and the C....
.