Aberrant signaling: overlapping and interacting, the pathways that control the cell cycle can resemble a plate of spaghetti, and when dysfunctional, can lead to cancer.

Dissecting the mechanisms of cancer has revealed an ever-increasing number of interconnecting pathways that leaves even those in the field dizzy with the effort to keep up. In theory, it's simple. In an ideal world, cell division, survival, and death are in sync, promoting homeostasis with neither unregulated growth nor inappropriate cell loss. However, the real cellular world is laden with oncogenes and tumor suppressor genes whose products interact in overlapping pathways that, when dysfunctional, can lead to cancer.

Despite tremendous progress in unraveling these networks, researchers have their wore cut out for them. Daniel Haber, director of the Massachusetts General Hospital Cancer Center, explains: "We now have tools and approaches that should make progress even faster, but it's hard to be patient." Patience, however, is the prescription to fully understanding the mechanisms behind transformation of normal cells to cancer cells and perversion of normal tissue into malignant tumors. One by one, the genetic pathways are being elucidated.

THE FIRST OF MANY The retinoblastoma (Rb) protein could be called the cell-cycle master switch. Cyclin-dependent kinases (CDKs) phosphorylate Rb, turning on cell proliferation. (1) Otherwise Rb is bound to [E.sub.2]F, a transcription factor, sequestering it from activating genes required for cell proliferation. Like other proteins once thought to have one job, Rb has several; it is implicated in DNA replication, differentiation, DNA repair, cell-cycle checkpoints, and apoptosis. In fact, it may interact with more than 100 different cellular proteins.

Rb was the first tumor suppressor gene to be cloned, although how it acts remains unclear. People with germline mutations develop the retinal tumors that give retinoblastoma (Rb) its name--loss of the second Rb allele is the rate-limiting step. Rb is also mutated in diverse sporadic cancers, including small-cell lung carcinoma and osteosarcoma. Plus, alterations in Rb regulatory proteins, such as p16, cyclin D, and CDK4/6, are common in a spectrum of human tumors. "Rb [is] ... downstream of p16 and cyclinD/CDK4, all of which have been found deregulated in cancer," says Marie Classon, staff scientist at Massachusetts General Hospital's cancer center. Taken together, Rb pathway perturbation is a common and significant event in tumorigenesis.

THE DNA DAMAGE RESPONSE Dysfunction of DNA repair and DNA damage checkpoint pathways is largely responsible for genetic instability, a hallmark of cancer cells. Originally defined as pathways that slow the cell to allow time for repair, DNA damage checkpoints also help prevent chromosomal instability. Recently, mushrooming data expose a nexus of overlapping processes called the DNA damage response pathway (DRP). Rather than merely slowing the cell cycle when DNA is damaged, the DRP is multifunctional, controlling repair, telomere composition and length, transcriptional programs, and in some cases, apoptosis. (2) "It is now recognized that …