The Cell Cycle Clock and Cancer

Most, perhaps all, human cancers grow inappropriately not only because signaling pathways are disturbed but also because the so-called cell cycle clock becomes deranged. The clock is composed of an assembly of interacting proteins in the nucleus, and normally integrates messages from the stimulatory and inhibitory pathways. If the stimulatory messages win out, the cell moves through the cycle of growth and division. Progression through the four stages is driven by means of a variety of molecules. The two essential components are proteins called cyclins and cyclin-dependent-kinases (CDKs), which associate with one another and initiate entrance into the various stages of the cell cycle. We will focus primarily on cyclin D and its role in the cell cycle.

A crucial step in the cell cycle occurs late in G1 at the Restriction point (R), which is the point when the cell decides to commit itself to completing the cycle (Fig. A). For the cell to pass through R and enter S, a molecular “switch” must be flipped from “off” to “on.”

Fig. A. Stages of the cell cycle.

How does the molecular switch work? As levels of cyclin D (and later E) rise, these proteins combine with and activate the appropriate cyclin-dependent kinases (CDKs) (Fig. B1). The activated cyclin-CDK complex catalyzes the transfer of phosphate groups from ATP to a powerful growth-inhibitory protein called pRB, the master brake of the cell cycle clock. When the pRB “brake” protein lacks phosphates, it actively blocks continuing the cell cycle and keeps the switch in the “off” position. It does so by sequestering and inactivating other proteins called transcription factors. (Transcription factors turn on specific genes.) But after the cyclin-CDK complexes transfer enough phosphates to pRB, the pRB brake is inhibited and stops working; it releases the transcription factors (Fig. B3), freeing them to turn on certain genes, and the various proteins required for continued progression through the cell cycle are j produced.

Fig. B. A molecular “switch.”

How does this relate to cancer? Overactivity of the stimulatory proteins such as cyclin D, cyclin E, and certain CDKs have been implicated in many human cancers. Breast cancer cells, for instance, often produce excesses of cyclins D and E. Inactivation of certain inhibitory proteins has also been found. Certain cervical cancer cells, for instance, have dysfunctional pRB proteins. The net effect of any of these changes is that the clock begins to spin out of control, ignoring any external warnings to stop. The result is excessive proliferation of cells––i.e., a cancerous tumor. If investigators can find ways to impose clamps on the cyclins and CDKs active in the cell cycle, they may be able to halt cancer cells in their tracks.

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