Immune disorders

Artemis deficiency; Severe combined immunodeficiency due to DNA-PKCS deficiency (SCID)

Artemis Deficiency is linked to inhibition to DNA repair mechanisms and can be associated with inflammatory bowel disease. Severe Combined Immunodeficiency Due to Dna-Pkcs Deficiency is an immunodeficiency disorder. C1D to DNAPK interaction can be inhibited with the L1510P, or the E1516P + L1517D mutations. Radiation sensitivity and partially inhibited binding of DSB to DNAPK occurs with the mutation T2609A, but only when in association with the reduction of phosphorylation mutation S2612A mutation. If the mutations T2638A and T2647A occur in conjunction then phosphorylation is reduced, and DNAPK is constitutively active but would also be sensitive to radioactivity.
 

DNAPK appears to be a tumour suppressor protein (TSP). The active form of the protein kinase normally acts to inhibit tumour cell proliferation until damage to DNA can be repaired. Therefore, it can play a role to facilitate tumour cell survival under conditions of radiation and chemotherapy.
 

TranscriptoNET (www.transcriptonet.ca) analysis with mRNA expression data retrieved from the National Center for Biotechnology Information's Gene Expression Omnibus (GEO) database, which was normalized against 60 abundantly and commonly found proteins, indicated altered expression for this protein kinase as shown here as the percent change from normal tissue controls (%CFC) as supported with the Student T-test in the following types of human cancers: Bladder carcinomas (%CFC= +152, p<0.0002);Cervical cancer (%CFC= -54, p<0.0001); Cervical cancer stage 2B (%CFC= -62, p<0.089); Colon mucosal cell adenomas (%CFC= +71, p<0.0001); Gastric cancer (%CFC= +219, p<0.0001); Lung adenocarcinomas (%CFC= +78, p<0.0001); Malignant pleural mesotheliomas (MPM) tumours (%CFC= +50, p<0.043); Oral squamous cell carcinomas (OSCC) (%CFC= +124, p<0.0001); Skin fibrosarcomas (%CFC= +138, p<0.066); Skin melanomas - malignant (%CFC= +115, p<0.0001); Skin squamous cell carcinomas (%CFC= +84, p<0.09); T-cell prolymphocytic leukemia (%CFC= +110, p<0.035); and Vulvar intraepithelial neoplasia (%CFC= +116, p<0.011).

Insertional mutagenesis studies in mice have not yet revealed a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.06 % in 24904 diverse cancer specimens. This rate is only -26 % lower than the average rate of 0.075 % calculated for human protein kinases in general.

Highest percent mutation rates per 100 amino acids length in human cancers: 0.29 % in 1052 large intestine cancers tested; 0.19 % in 555 stomach cancers tested; 0.14 % in 602 endometrium cancers tested; 0.13 % in 805 skin cancers tested; 0.1 % in 1727 lung cancers tested; 0.09 % in 814 upper aerodigestive tract cancers tested; 0.07 % in 605 oesophagus cancers tested; 0.07 % in 500 urinary tract cancers tested; 0.05 % in 1270 liver cancers tested; 0.04 % in 1439 breast cancers tested; 0.03 % in 878 ovary cancers tested; 0.03 % in 1203 kidney cancers tested; 0.03 % in 1173 pancreas cancers tested.

None > 7 in 20,763 cancer specimens

Over 26 deletions, 10 insertions and 2 complex mutations are noted on the COSMIC website.