Canonical Smad Pathway Analysis

Initially called protein 17B, FGFR3 was discovered based on the similarities Paper 1 discovered FGFR3 through the use of homologous genes of other FGFRs. Regions such as the kinase domain and the C terminus were used to test the extent of homology between Protein 17B and the FGFRs. Paper 1 used a human cDNA library which was hybridized in low stringency. Then under high stringency, a partial FGFR3 clone was used as a probe. The DNA was cloned using dideoxynucleotide chain termination method. A mutation in the FGFR3 gene causes a premature activation of the STAT pathway which also leads to the premature production of phoshorylated Stat1 protein. The phophorylated Stat1 protein encodes genes for cell cycle inhibition, these leads to a decreased number of chondrocytes and hence shorter skeletal

The FBN1 gene is responsible for providing instructions for the production of fibrillin-1, which is a protein that is secreted into the matrix of connective tissue (“FBN1,” 2015). Therefore, a mutation in this gene can cause the excessive production of fibrillin-1, and when fibrillin-1 binds to other proteins they form threads called microfibrils. Microfibrils contain a growth factor called transforming growth factor beta or TGF-β (“FBN1,” 2015), so when there is an increase of TGF-β, problems with the connective tissue throughout the body can occur (“What is Marfan Syndrome? | The Marfan Foundation,” n.d.), more of these problems will be elaborated upon further in the report. The genetic mutation in the FBN1 gene is usually hereditary, but it is possible for one to be the first in their family to have this genetic mutation. If one has this mutation

In order to understand more about AMPK-dependent phosphorylation of endogenous ULK1 on Ser555, primary mouse embryonic fibroblasts (MEFs) with AMPK and ULK1 deficiency and matched control wild type MEFs. The cells were also treated with AMP-mimetic aminoimadazole carboxamide ribonucleotide (AICAR). The cells were placed under a 12 hour starvation period, and the cell death was scored using

Molecular Cell Biology, 7th Edition, 2013, Lodish, Berk, Kaiser, Krieger, Bretscher. Ploegh, Amon, and Scott. W.H. Freeman and Company (ISBN-13: 978-1-4292-3413-9)

The oligonucleotide antisense matches complementary to the region 107–128 of the human Smad7 mRNA sequence, and its

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Promoting or inhibiting the transcription of genes that code for the synthesis of cellular proteins intracellular second-messenger system are correct

Mutations that affect this cascade are thus of primary importance. There are three main genes, APP, PS1, and PS2, that when mutated alter the

Mammalian target of rapamycin (mTOR) is a serine/threonine kinase in which this catalytic subunit forms into two distinct multiprotein complexes, mTORC1 and mTORC2 (Laplante et al., 2009 and Bar-Peled et al., 2014). The two multiprotein complexes share many similarities, but are still distinct from one another. Both complexes regulate anabolic processes such as cell survival, metabolism and proliferation. However, mTORC2 is known to play a key role in cytoskeleton organization to regulate cellular spatial growth (Laplante et al., 2009 and? ). While they share many functions, only mTORC1 coordinates these anabolic functions with upstream inputs such as: growth factors, energy status, and amino acid availability. mTORC1 is composed of five components: mTOR, the catalytic subunit; regulator-associated protein of mTOR (RAPTOR), scaffolding subunit; mammalian lethal with Sec13 protein 8 (mLST8); and two endogenous kinase inhibitors proline-rich AKT substrate 40kDa (PRAS40) and DEP-domain-containing mTOR-interacting protein (DEPTOR) (Laplante et al., 2009 and Bar-Peled et al., 2014 (5,6,7,8,9) and more). In order to effectively control cellular physiology, mTORC1 activation triggers a downstream signaling cascade to control such anabolic processes as protein synthesis and ribosomal biogenesis (). However, mTORC1 signaling cascade is regulated by small GTPase Rheb located at the lysosome surface and functions as a mTORC1 kinase activity stimulator under its active GTP-bound state (Bar-Peeled et al., 2014). Nevertheless, Rheb is also negatively regulated by tuberous sclerosis complex (TSC) 1 and 2 by exerting is

Sufu has the ability to bind to GLI1, GLI2 and GLI3 proteins. It is theorized that GLI proteins are binded to Sufu in a head to tail orientation. GL1 is solely found in the nucleus, whereas Sufu can be found expressed in both the nucleus and the cytoplasm. However when they are both expressed together, Sufu brings the GLI1 into the cytoplasm which forces the nucleus to limit its transcription activity. The cytoplasm anchoring model suggests that GLI1 is anchored to the cytoplasm with the help of Sufu. Likewise, Sufu plays a similar role in Drosophilia by halting nuclear processes. Thus, it is found that Sufu travels back and forth between the cytoplasm and nucleus in both Drosophilia and mammals. A second model of Sufu function in mammals suggests the Sufu gene holds the ability of repressing transcription of GLIs. A study found that Sufu restricts GLI transcription by enlisting the help of the mSin3A HDAC corepressor complex. Sufu was also found to increase the ability of GLI1 to bind to DNA. Therefore, simply repressing the Sufu gene is enough to activate GLI transcription, alluding to its key role in the negative regulation of the SHH signaling

It took an additional six years for researchers to glimpse at the functions provided by SMN1. Meister et al. categorized the SMN1 protein an essential to promote correct assembly of U12 small ribonucleoproteins (snRNPs). In genetics, snRNPs are nucleic proteins responsible for the splicing of premature ribonucleic acid chains (pre-mRNA) derived from genes. Without correct splicing, mature ribonucleic acid chains (mRNAs) produce dysfunctional proteins when translated. In this case, splicing functionality of U12 - intron containing transcripts is lost, and because the transcript is wrongly coded, its translation will produce a functionless protein. Hence, loss of SMN1 results in an inability form U12 snRNPs splicing complexes, and reduced splicing functionality results in loss of U12 - intron splicing functionality (Patel and Steitz, 2003).

In signaling pathways, it can be observed that SMAD1/5/9 is potentiated by activin A. SMAD2 is induced by activin A but not potentiated.

According to Arquint and Nigg evidence indicates that PLK4, STIL, and SAS4 play a important role in the initiation of centriole duplication.

The Yeast two-hybrid system was used in this investigation to find which of four DNA inserts codes for a protein able to interact through protein-protein interactions with the protein encoded by the Bub1B gene. The protein encoded by the Bub1B gene is a kinase, which has a role in the formation of the mitotic spindle checkpoint ‘Davenporta et al. (1998)’

Discuss in detail the effects that an activating mutation in the IKBKB gene would be expected to have on the downstream signalling pathway components and target gene expression, and how these effects are measured in the article.