User:Jarrod Heffernan/sandbox

Article Evaluation
Article: Histone

Notes/Observations:

- Introduction section could use more references; seems like stating information that isn't necessary.

- Some grammatical errors, particularly in final paragraph of the structures and variants heading.

- Good sourcing later in article when discussing particular histone methylation sites and their apparent genomic effects.

- CK2's role in apoptosis, or more specifically anti-apoptotic signaling
CK2 has been found to play a role in regulation between phases in the cycle, notably between G1/S and G2/M phases. Due to CK2’s association with the mitotic spindle it is believed that it has a larger role in G2/M progression when compared to G1/S progression. Another indication of involvement in cell cycle regulation the interaction between phosphorylated (activated) CK2 and a known cell cycle regulatory protein Pin1.

Inducing forced expression of the CK2alpha sub-units (both prime and not prime) yielded decreased cell proliferation because these forms of CK2 were both catalytically inactive. Furthermore the catalytically inactive form of CK2aplha’ is shown specifically to have the insufficient cell proliferation. Mice with CK2alpha’ -/- were shown to have a predisposition to apoptosis; no rescuing of the phenotype was observed with a normal functioning CK2alpha and inactive CK2alpha’. CK2 is found to protect proteins from caspase-mediated degradation via phosphorylation, indicating its anti-apoptotic function. Paired with this inhibition of native apoptotic inhibition CK2 is also found to protect cells from drug-induced apoptosis usually similar methods. Similar consensus sequences between CK2 phosphorylation sites and recognition sequence of caspase.

- Role in tumorigenesis as well as inhibitors of CK-2 as potential cancer therapy.
Acts as an anti-apoptotic protein by protecting other proteins via phosphorylation. Down regulation of CK2 may allow cancer therapies to be effective in tumors they previously had no effect on. Cancers often present with increased expression of CK2, increasing the survival chances of the cancerous cells.

- Other possible existences of CK-2 sub-units outside of the tetramer as well as small changes to the existing snippet on structure of CK-2.
Individual subunits have been found to exist outside of the tetramer. There is a difference in function between the catalytic subunits as well, between alpha and alpha’. In humans we only have one isoform of the beta regulatory subunit but it is worth noting there has been other isoforms found in other organisms.

-phosphorylation function of CK-2 and what big-picture effects that may infer
Active phosphorylation of cell cycle proteins; may incur improper growth if too much phosphorylation occurs. Plays a role in multiple stress signaling pathways including phosphorylation of p53 and interactions with MAP kinase. Traditionally known as a serine/threonine kinase CK2 can also phosphorylate tyrosine residues giving it a dual specificity; but the phosphorylation of tyrosine is not as favourable or frequent as serine/threonine.

Rough Copy of full article
Casein kinase 2 (EC 2.7.11.1)(CK2/CSNK2) is a serine/threonine-selective protein kinase that has been implicated in cell cycle control, DNA repair, regulation of the circadian rhythm, and other cellular processes. De-regulation of CK2 has been linked to tumorigenesis as a potential protection mechanism for mutated cells. Proper CK2 function is necessary for survival of cells as no knockout models have been successfully generated. 5

Structure
CK2 typically appears as a tetramer of two α subunits; α being 42 kDa and α’ being 38 kDa, and two β subunits, each weighing in at 28 kDa.5 The β regulatory domain only has one isoform3 and therefore within the tetramer will have two β subunits. The catalytic α domains appear as an α or α’ variant and can either be formed in a homodimer (α & α, or α’ & α’) formation or heterodimer formation (α & α’).3 It is worth noting that other β isoforms have been found in other organisms but not in humans. 3

The α subunits do not require the β regulatory subunits to function, this allows dimers to form of the catalytic domains independent of β subunit transcription. The presence of these α subunits does have an effect on the phosphorylation targets of CK2.4 A functional difference between α and α’ has been found but the exact nature of differences isn’t fully understood yet. An example is that Caspase 3 is preferentially phosphorylated by α’ based tetramers over α based tetramers.4

Function
CK2 is a protein kinase responsible for phosphorylation of substrates in various pathways within a cell; ATP or GTP can be used as phosphate source.5 CK2 has a dual functionality with involvement in cell growth/proliferation and suppression of apoptosis.5 CK2s anti-apoptotic function is in the continuation of the cell cycle; from G1 to S phase and G2 to M phase checkpoints.3 This function is achieved by protecting proteins from caspase-mediated apoptosis via phosphorylation of sites adjacent to the caspase cleavage site, blocking the activity of caspase proteins. CK2 also protects from drug-induced apoptosis via similar methods but it is not as well understood.3 Knockdown studies of both α and α’ subunits have been used to verify this anti-apoptotic function.

Important phosphorylation events also regulated by CK2 are found in DNA damage repair pathways, and multiple stress-signaling pathways. Examples are phosphorylation of p53 or MAPK, which both regulate many interactions within their respective cellular pathways.

Another indication of separate function of α subunits is that mice that lack CK2α’ have a defect in the morphology of developing sperm.[2]

Regulation of CK2
Although the targets of CK2 are predominantly nucleus-based the protein itself is localized to both the nucleus and cytoplasm.5 Casein kinase 2 activity has been reported to be activated following Wnt signaling pathway activation.[1] A Pertussis toxin-sensitive G protein and Dishevelled appear to be an intermediary between Wnt-mediated activation of the Frizzled receptor and activation of CK2. Further studies need to be done on the regulation of this protein due to the complexity of CK2 function and localization.

Role in Tumorigenesis
Among the array of substrates that can be altered by CK2 many of them have been found in increased prevalence in cancers of the breast, lung, colon, and prostate.4 An increased concentration of substrates in cancerous cells infers a likely survival benefit to the cell, and activation of many of these substrates requires CK2. As well the anti-apoptotic function of CK2 allows the cancerous cell to escapes cell death and continue proliferating. Having roles in cell cycle regulation may also indicate CK2’s role in allowing cell cycle progression when normally it should have been ceased. This also promotes CK2 as a possible therapeutic target for cancer drugs. When added with other potent anti-cancer therapies, a CK2 inhibitor may increase the effectiveness of the other therapy by allowing drug-induced apoptosis to occur at a normal rate.