Cancer results from the acquisition of mutations in genes that function as oncogenes (the encoded protein promotes cell growth) or tumor suppressors (the encoded protein regulates the cell growth cycle), leading to their aberrant activation or repression, respectively. Although individual cancer cells have a unique etiology, or blueprint of genetic mutations that confer upon them the ability for unregulated cell proliferation, researchers have identified a few usual suspects: genes that are mutated in a large number of human cancers. For example, the Ras oncogene is activated in roughly one third of all human tumors, while the p53 tumor suppressor gene is inactivated in half.
Dr. Hiroaki Kiyokawa and colleagues have found that expression of a gene called Cdk4 is essential for Ras-induced cancer development, regardless of p53 status or the presence of another frequently mutated tumor suppressor gene, Ink4a/Arf.
The Cdk4 protein promotes progression through the G1 (initial) phase of the cell growth cycle. Accumulating evidence has implicated aberrant Cdk4 activation in the development of a variety of human tumors, including breast cancer, glioblastomas, sarcomas, and melanomas. Thus, Dr. Kiyokawa and colleagues generated mouse cells deficient in Cdk4 in order to determine its role in tumorigenesis.
Dr. Kiyokawa and colleagues deleted the Cdk4 gene in mouse embryonic fibroblast cells (MEFs; connective tissue cells derived from mouse embryos) in a variety of different genetic backgrounds, and assayed these cells for tumorigenicity both in cell culture (via their ability to divide indefinitely, or act "immortal") and in live mice (via their ability to form solid tumors when injected into immunocompromised mice). The researchers found that while Cdk4-deficient cells grow and divide normally under standard conditions, once the Ras oncogene is activated, these cells retreat into a cancer-resistant state of terminal growth arrest, called senescence. Ras-expressing Cdk4-deficient cells also senescence when either the p53 or Ink4a/Arf tumor suppressor gene is inactivated, demonstrating that Cdk4 is required for tumorigenesis even when commonly mutated tumor suppressor genes are non-functional.
This discovery that diminished Cdk4 expression steers cells into a protective state of senescence against oncogenes like Ras has significant therapeutic implications. In light of the frequency with which the Ras oncogene is expressed and the p53 or Ink4a/Arf tumor suppressor pathway is disabled in human tumors, the deliberate suppression of Cdk4 activity may provide an alternate point of entry for doctors to regulate the cell growth cycle and halt tumorigenesis.
Journal
Genes & Development