C-JUN

Andrew Rebeyka

C-JUNC-JUN

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IntroductionIntroduction

The c-Jun protein is a member of transcription factors which consist of a basic region leucine zipper region . Originally identified by its homology to v-jun, the oncogene from the avian sarcomoa virus Bossy-Wetzel, E., Bakiri, L., Yaniv, M. (1997). Induction of apoptosis by the transcription factor c-Jun. EMO Journal. Vol.16;7. 1695-1709 </ref>. All these leucine zipper factors bind to DNA in one of two states: homo or heterodimers . In conjunction with the c-Fos protein these two proteins bind to specific regions of DNA strands. Together these two proteins form the c-fos/c-jun complex which help regulate cell growth and differentiation . the members of the jun and fos families include three Jun proteins and four Fos proteins (c-Jun, JunB, JunD,c-Fos, Fos-B, Fra1, and Fra2) PMID:12798298 </ref>. Regulation of the complex iteslf is done by interactions between the protein and DNA in addition to the protein-protein interactions between each of the leucine zipper domains .

Structure OverviewStructure Overview

File:1jun.png

Figure 1. A 3-D representation of the two alpha helices which form a coiled coil [1].

The structure of c-Jun is comprised of a leucine zipper as previously stated. This dimerization motif may be in one of two classes, both of which are required for DNA-binding transcription factors; the basic-domain leucine zipper proteins (bZIP) and the basic helix loop-helix-leucine zipper proteins(bHLH-ZIP) A Junius, F.K., Mackay, J.P., Bubb, W.A., Jensen, S.A., Weiss, A.S., King, G.F. 2006. Nuclear Magnetic Resonance Characterization of the Jun Leucine Zipper Domain: Unusual Properties of Coiled-Coil Interfacial Polar Residues?</ref>. As can be been in the figure XXXXX, the strand becomes an elongated coiled coil. This is formed by residues at the a and d positions in each of the two monomers, whereby they create hydrophobic centers which conform to the "knobs into holes" model by Crick. . amino acids at these a and d positions are each surrounded by 4 additional residues from adjacent a-helix monomer .

the a and d residues each exhibit varying types of packing in terms of this "knobs into holes" theory. According to Harbury et al.(24) the leucines at the a positions are packed "parallel" in such a way that the C-alpha-C-beta bond vector lies in a parallel manner to the C-alpha-C-alpha vector at the base of the acceptor hole on adjacent helix . Whereas the opposite is true for the leucines in the d positions. Here the residues are packed in a "perpendicular" nature . The bond vector of the C-alpha-C-beta pack approximately perpendicular to the C-alpha-C-alpha vector at the base of the hole of the second helix in which it packs . therefore only the leucine side chains in the a positions, which point away from the boundary, make van der Waals interactions .

This protein is a dimer that is completely symmetrical . It is comprised of a coiled coil of two alpha helices .

C-Jun binds to specific DNA sites either in the homodimer or heterodimer forms with the aid of C-Fos protein . C-Jun is a transcriptional activator . C-jun, with the aid of C-Fos represents a crucial union between normal and uncontrolled cell growth as their combined role in the transduction of afferent growth signals the response of specific genes .

Protein FunctionProtein Function

The primary function of c-Jun is in regards to DNA transcription. Specifically, the protein is involved in proliferation, apoptosis, oncogenic transformation and various cellular processes . for instance cells which lack an allele for c-jun show stunted growth both in vitro and in vivo . whereas a prolonged and therefore strong induction of c-jun has been in response to such things as tumor necrosis factor, stress inducing stimuli such as UV .

Protein RegulationProtein Regulation

Changes made in the phosphorylation state of specific amino acids is one means by which c-Jun regulates transcription PMID:8165146 </ref>. To date two seperate sites of phosphorylation have been identified. at the N-terminal end are the amino acids Ser63 and Ser73, which are phosphorylated in response to ras expression. When ras is expressed, and Ser63 and Ser73 are phosphorylated, transcriptional activity of c-Jun increases. the second site is located at the C-terminal which is very close in proximity to the DNA binding domain. Here the residues are Thr214, Ser226, and Ser 232 . Unlike the two serines at the N-terminal end, phosphorylation at the C-terminal end inhibits DNA binding to c-Jun . therefore with the expression of such oncogenes as ras lead to dephsphorylation of these three residues.

Psychological InfluencesPsychological Influences

The stress-induced signalling cascade may also active c-Jun by phosphorylation. the N-ternminal protein kinase phosphorylates Ser63 and Ser73 PMID:10064599 </ref> . Another mechanism for the activation however is interestingly through intracellular calcium concentrations. increasing these concentrations by opening the L-type voltage gated calcium channels It was found that the N-terminus contains both calcium and stress-regulated transcriptional activation domains . According to the study,distinct mechanisms of c-Jun control function by calcium and stress signals .