Cancer

Variations in PKCa’s gene sequence may also associate with increased susceptibility to asthma.
 

Pituitary tumours, invasive

PKCa may be an oncoprotein (OP). PKCa has been implicated in tumorigenesis, as it is strongly activated by many different tumour promoting compounds, such as phorbol esters and teleocidins. While these compounds promote binding of PKC isoforms to the plasma membrane of cells, which stimulates their phosphotransferase activity, these agents also induce rapid down-regulation of PKC isoforms. Consequently, it is controversial whether PKCa is an oncoprotein or a tumour suppressor protein. PKCa is highly expressed in several cancers, including malignant breast cancers and gliomas. An N294G point mutation in PKCa has been linked to the invasive phenotype of these tumours, indicating a gain-of-function in the kinase catalytic phosphotransfersase activity. Increased expression of PKCa has been observed in adenomatous pituitaries, with highest expression in invasive pituitary tumours. A point mutation was also identified in 4 invasive pituitary tumours. Furthermore, PKCa appears to stimulate cell proliferation, because many of its direct targets, such as Raf1, BCL2, and CSPG4, participate in growth factor signalling pathways and PKC activators induce the downstream activation of ERK1/2 (MAPK3/1) and RAP1GAP.
 

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: Barrett's esophagus epithelial metaplasia (%CFC= +94, p<0.057); Brain oligodendrogliomas (%CFC= -97, p<0.02); and Oral squamous cell carcinomas (OSCC) (%CFC= +57, p<0.079). The COSMIC website notes an up-regulated expression score for PKCa in diverse human cancers of 490, which is close to the average score of 462 for the human protein kinases. The down-regulated expression score of 22 for this protein kinase in human cancers was 0.4-fold of the average score of 60 for the human protein kinases.

Insertional mutagenesis studies in mice support a role for this protein kinase in mouse cancer oncogenesis.

Percent mutation rates per 100 amino acids length in human cancers: 0.09 % in 25491 diverse cancer specimens. This rate is only 18 % higher 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: 0.48 % in 805 skin cancers tested; 0.45 % in 1093 large intestine cancers tested; 0.32 % in 602 endometrium cancers tested; 0.25 % in 589 stomach cancers tested; 0.12 % in 1941 lung cancers tested.

None > 5 in 20,654 cancer specimens

Only 6 deletions, no insertions or complex mutations are noted on the COSMIC website. About 25% of the point mutations are silent and do not change the amino acid sequence of the protein kinase.