As mentioned in Chapter 1, growth factors transduce signals that stimulate the orderly progression of cells through the various phases of the cell cycle, the process by which cells replicate their DNA in preparation for cell division. You will recall that progression of cells through the cell cycle is orchestrated by cyclin-dependent kinases (CDKs), which are activated by binding to cyclins, so called because of the cyclic nature of their production and degradation.
http://ebooksmedicine.net
The CDK-cyclin complexes phosphorylate crucial target proteins that drive cells forward through the cell cycle. While cyclins arouse the CDKs, CDK inhibitors (CDKIs), of which there are many, silence the CDKs and exert negative control over the cell cycle. Expression of these inhibitors is downregulated by mitogenic signaling pathways, thus promoting the progression of the cell cycle.
There are two main cell cycle checkpoints, one at the G1/S transition and the other at the G2/M transition, each of which is tightly regulated by a balance of growth-promoting and growth-suppressing factors, as well as by sensors of DNA damage (Chapter 1). If activated, these DNA-damage sensors transmit signals that arrest cell cycle progression and, if cell damage cannot be repaired, initiate apoptosis. Once cells pass through the G1/S checkpoint, they are committed to undergo cell division. Understandably, then, defects in the G1/S checkpoint are particularly important in cancer, since these lead directly to increased cell division. Indeed, all cancers appear to have genetic lesions that disable the G1/S checkpoint, causing cells to continually reenter the S phase. For unclear reasons, particular lesions vary widely in frequency across tumor types, but they fall into two major categories.
Gain-of-function mutations involving CDK4 or D cyclins. Mishaps increasing the expression of cyclin D or CDK4 are common events in neoplastic transformation. The cyclin D genes are overexpressed in many cancers, including those affecting the breast, esophagus, liver, and a subset of lymphomas and plasma cell tumors. Amplification of the CDK4 gene occurs in melanomas, sarcomas, and glioblastomas. Mutations affecting cyclins B and E and other CDKs also occur, but they are much less frequent than those affecting cyclin D and CDK4.
Loss-of-function mutations involving CDKIs. CDKIs frequently are disabled by mutation or gene silencing in many human malignancies. For example, germline mutations of CDKN2A, a gene that encodes the CDK inhibitor p16, are present in 25% of melanoma-prone kindreds, and acquired deletion or inactivation of CDKN2A is seen in 75% of pancreatic carcinomas, 40% to 70% of glioblastomas, 50% of esophageal cancers and certain leukemias, and 20% of non–small cell lung carcinomas, soft-tissue sarcomas, and bladder cancers.
A final consideration of importance in a discussion of growth-promoting signals is that the increased production of oncoproteins does not by itself lead to sustained proliferation of cancer cells. There are two built-in mechanisms, cell senescence and apoptosis, that oppose oncogene-mediated cell growth. As discussed later, genes that regulate these two braking mechanisms must be disabled to allow the action of oncogenes to proceed unopposed.
Proto-oncogenes: normalcellulargeneswhoseproductspromotecellproliferation
Oncogenes: mutantoroverexpressedversionsofprotooncogenesthatfunctionautonomouslywithoutarequirementfornormalgrowth-promotingsignals
Oncoproteinspromoteuncontrolledcellproliferationbyseveralmechanisms:
Stimulus-independentexpressionofgrowthfactoranditsreceptor,settingupanautocrineloopofcellproliferation(e.g.,PDGF–PDGFreceptorinbraintumors)