Question

Discuss with examples the genetic mechanisms that deregulate the cell cycle in tumors.(Min 2 and a half pages)

Answer 1

The ultimate outcome of all growth-promoting stimuli
is the entry of quiescent cells into the cell cycle. Cancers may become autonomous if the genes that drive the cell cycle become dysregulated by mutations or amplification. Before further consideration of this aspect of carcinogenesis, a brief review of the normal cell cycle is warranted.

The Normal Cell Cycle
Cell proliferation is a tightly controlled process that
involves a large number of molecules and interrelated
pathways. The replication of cells is stimulated by growth factors or by signaling from ECM components through integrins. To achieve DNA replication and division, the cell goes through a tightly controlled sequence of events known as the cell cycle. The cell cycle consists of G1 (presynthetic), S (DNA synthesis), G2 (premitotic), and M (mitotic) phases. Quiescent cells that have not entered the cell cycle are in
the G0 state. Each cell cycle phase is dependent on the proper activation and completion of the previous ones and the cycle stops at a place at which an essential gene func-tion is deficient. Because of its central role in maintaining tissue homeostasis and regulating physiologic growth processes such as regeneration and repair, the cell cycle has multiple checkpoints, particularly during emergence from
G0 into G1 and the transition from G1 to S phase.
Cells can enter G1 either from G0 (quiescent cells) or after completing mitosis (continuously replicating cells). Quiescent cells must first go through the transition from G0 to G1, the first decision step, which functions as a gateway to the cell cycle. Cells in G1 progress through the cell cycle and reach a critical stage at the G1-S transition, known as a restriction point, a rate-limiting step for replication. On
passing this restriction point, normal cells become irreversibly committed to DNA replication. The cell cycle is tightly controlled by activators and inhibitors.
• Progression through the cell cycle, particularly at the
G1-S transition, is regulated by proteins called cyclins, so called because of the cyclic nature of their production and degradation, and associated enzymes, the cyclin-dependent kinases (CDKs). CDKs acquire catalytic activity by binding to and forming complexes with the cyclins.
The orderly progression of cells through the various
phases of the cell cycle is orchestrated by CDKs, which are activated by binding to the cyclins.
• The CDK–cyclin complexes phosphorylate crucial target proteins that drive the cell through the cell cycle. On completion of this task, cyclin levels decline rapidly.
More than 15 cyclins have been identified; cyclins D, E,
A, and B appear sequentially during the cell cycle and
bind to one or more CDKs. The cell cycle may thus be
seen as a relay race in which each leg is regulated by a distinct set of cyclins: As one set of cyclins leaves the track, the next set takes over. Activated CDKs
in these complexes drive the cell cycle by phosphorylating proteins that regulate cell cycle transitions. One such protein is the retinoblastoma protein (Rb)
• The activity of CDK–cyclin complexes is regulated
by CDK inhibitors (CDKIs), which enforce cell cycle
checkpoints. Embedded in the cell cycle are surveillance mechanisms that are geared to sensing damage to DNA and chromosomes. These quality control checks are called checkpoints; they ensure that cells with damaged DNA or chromosomes do not complete replication. The G1-S checkpoint monitors the integrity of DNA before DNA replication, whereas the G2-M checkpoint checks
DNA after replication and monitors whether the cell can safely enter mitosis. When cells sense DNA damage, checkpoint activation delays the cell cycle and triggers DNA repair mechanisms. If DNA damage is too severe to be repaired, the cells are eliminated by apoptosis, or enter a nonreplicative state called senescence, primarily through p53-dependent mechanisms, discussed later on.
Mutations in genes regulating these checkpoints allow
cells with damaged DNA to divide, producing daughter
cells carrying mutations.
• There are several families of CDKIs. One family,
composed of three proteins called p21 (CDKN1A),
p27 (CDKN1B), and p57 (CDKN1C), inhibits the CDKs
broadly, whereas the other family of CDKIs has selective effects on cyclin CDK4 and cyclin CDK6. The four members of this family—p15 (CDKN2B), p16 (CDKN2A), p18 (CDKN2C), and p19 (CDKN2D)—are sometimes called INK4 (A to D) proteins.

Alterations in Cell Cycle Control Proteins in Cancer Cells.

With this background, it is easy to appreciate the mutations that dysregulate the activity of cyclins and CDKs would favor cell proliferation. 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.
• Mishaps increasing the expression of cyclin D or CDK4 seem to be a common event 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 CDK4.
• The CDKIs frequently are disabled by mutation or gene silencing in many human malignancies. Germline muta-tions of CDKN2A are present in 25% of melanoma-prone kindreds. Somatically acquired deletion or inactivation of CDKN2A is seen in 75% of pancreatic carcinomas, 40% to 70% of glioblastomas, 50% of esophageal cancers, 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. So, genes that regulate these two braking mechanisms must be disabled to allow unopposed action of oncogenes.