Description: Lung cancer is the most common cause of cancer-related deaths in the United States, and in spite of the progress that has been made in understanding the molecular biology of the disease mortality rates have not decreased significantly. To a large extent this is due to the fact that lung tumors form metastases early when the primary tumor is small and less likely to be detected. What is needed are effective systemic therapies, and diagnostic tools to detect tumors at early, pre-metastatic stages.
Chromosomal deletions in tumors are usually taken to indicate the location of one or several tumor suppressor genes in the same region. We have identified a gene with several splice variants close to a chromosomal region that has been shown to be homozygously deleted in lung tumors. The first exon of the gene contains an evolutionary conserved predicted phosphorylation site for PKB/Akt, a key mediator of signal transduction processes involved in cell proliferation and survival. Using a synthetic 13-aa peptide as a substrate for recombinant PKB/Akt we have confirmed that the predicted threonine is a putative phosphorylation site for PKB/Akt. PKB/Akt can both promote proliferation and inhibit apoptosis through phosphorylation of key proteins like p21, the forkhead transcription factor, BAD, and others. Often this leads to inhibition or sequestration of the phosphorylated protein. Several other proteins known to be involved in proliferation or apoptosis, such as DAP kinase, Huntington protein, and several caspases, although not yet shown to be PKB substrates contain putative PKB phosphorylation sites.
The first six exons of the gene are ubiquitously expressed in all tissues and cell lines that we have screened. Alternative splicing of the first exon creates a transcript with shorter reading frame and a different protein product. In many cell lines and tissues the last internal exon is alternatively spliced onto exons downstream of the sixth exon to generate low expression levels of numerous alternative transcripts of which many are very long and some span the minimal region of homozygous deletion mentioned above. Preliminary results indicate that these variants are differentially expressed in tumors versus normal tissue.
The significance of the various splice variants of this gene is not clear yet, but preliminary experiments indicate that they are differentially expressed in normal tissue versus tumors. If changes in expression occur early in cancer development, this could facilitate early detection of cancer, and a diagnostic procedure or kit could be developed.
The fact that there is a putative PKB/Akt phosphorylation site in the first exon of our gene raises the possibility that its various splice variants function in the PKB/Akt cell survival pathway, which is up-regulated in many types of cancer. It appears to be the major pathway for survival of cancer cells. Thus our gene could become targets for new therapeutic strategies for chemotherapy and chemoprevention. We have unpublished data showing that the PKB/Akt pathway is activated in many early lesions (hyperplasia and dysplasia).
For more information please contact Kellen Sensor at 513-558-5621 or Kellen.Sensor@uc.edu