Millennium Review
Control of the cell cycle and apoptosis

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A brief description of the clock apparatus

The clock machinery is composed of two core components, cyclin-dependent kinases (cdks) and cyclins (Fig. 1). Like the great bulk of the cell's protein kinases, the cdks phosphorylate target proteins on critical serine and threonine sites. Protein kinases offer great opportunity for amplifying and broadcasting regulatory signals, in that a single kinase molecule can modify a number of distinct target proteins, phosphorylating hundreds or thousands of each species of protein in a short period of

G1 progression and the restriction point

The above description alone provides little insight into the physiology of cell growth control. The guiding concept here is that external mitogenic and antimitogenic signals are received by the cell; they are processed and funneled to the clock apparatus; and this apparatus responds by programming the advance of the cell through the various phases of its growth cycle. How does the clock machinery make this regulation possible and how is this regulation disturbed in tumour cells?

In fact, the

pRB and the R point transition

How is the R point decision executed, and what afferent signals converge on this decision? A diverse body of evidence accumulated over the past decade has shown that the retinoblastoma protein, pRB, is the molecular device that serves as the R point switch. When unphosphorylated or hypophosphorylated, pRB blocks the R point transition. Once phosphorylated, pRB loses much, if not all, of its growth-inhibitory powers and permits advance into late G1 and thence into the remainder of the cell cycle

Exogenous signals affecting pRB phosphorylation

As stated above, extracellular physiological signals affect the decision to transit the R point and this decision is executed through pRB phosphorylation. This must mean that extracellular signals directly control pRB phosphorylation, a speculation borne out by much evidence accumulated over the past five years.

Most dramatic is the evidence that mitogens directly and rapidly induce expression of cyclin D1, the first of the D-type cyclins to be discovered[12]. Once formed, cyclin D1, like other

Derangement of R point control in cancer cells

R point control is deranged in many and possibly all types of tumour cells. How precisely do the growth-deregulating lesions found in cancer cells affect this decision, or more specifically, how do they affect the known components of the cell cycle clock? A most obvious point of deregulation comes from the well-documented aberrations of the mitogen-activated pathway in many human tumours, perhaps in all of them. Once activated constitutively, this pathway can drive the expression of D-type

Control by intracellular signals

The cell cycle clock must respond to other signals beyond those conveyed by extracellular factors such as mitogens and antimitogens. Equally important are the signals that reveal the status of the cell's own internal metabolism and its genome. A well-organised cell physiology dictates that cell cycle advance is only appropriate and permissible when the intracellular household is in order.

The effects of genomic integrity on cell cycle advance have been intensively studied, if only because the

Apoptosis within the cell cycle clock

The above scenario suggests that two distinct machines operate within the cell, both under the control of p53. However, this implied separation between the cell cycle clock and the apoptotic machinery represents an over-simplification. The cell cycle clock apparatus itself can directly participate in triggering the apoptotic response.

This connection was first suggested by investigation of the E2F1 transcription factor. Genetically altered mice lacking the E2F1 gene develop lymphoid hyperplasias

Escape from cell senescence and apoptosis

The model of multistep tumour progression implies that clones of tumour cells must address and solve a succession of biochemical and cell regulatory problems en route to becoming fully malignant. Among these problems are an acquired independence from exogenous mitogenic stimulation, an acquired resistance to exogenous growth-inhibitory signals, and an acquired ability to resist apoptosis.

The first two of these problems can largely be solved by deregulating the cell cycle clock apparatus,

Precis and perspective

The deregulation of the cell cycle clock and the apoptotic apparatus as described here represents only a portion of the changes that are required to make a malignant cell. A cell clone on the way to becoming malignant gains substantial benefit from the cited alterations in its growth-regulating genes, including among other functional advantages: (i) mitogen independence and an ability to resist antimitogens; (ii) an ability to tolerate anoxia and other apoptosis-inducing conditions; (iii) an

Dr Ante Lundberg is a post-doctoral fellow at the Whitehead Institute for Biomedical Research, and a Research Fellow at Harvard Medical School. He received his B.Sc. degree in Biology from Massachusetts Institute of Technology, and his MD degree from Stanford Medical School. He completed his training in Internal Medicine at the Brigham and Women's Hospital, and in Adult Oncology at Dana-Farber Cancer Institute, both in Boston, Massachusetts, U.S.A. The goal of his research is to understand how

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      Thus, molecular mechanisms controlling progression through the restriction point are of central importance in governing entry into the cell cycle. The pRb, a tumor suppressor protein, is likely a key switch at the restriction point [52]. It blocks cell proliferation by sequestering and altering the function of E2F transcription factors that control the expression of set of genes essential for G1 to S phase transition (described below).

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      DNA ploidy retained independent statistical relevance at multivariate analysis. The cell cycle is positively controlled by the cyclin-dependent kinases [CDK]s and their regulator proteins termed cyclins [24]. Cyclin/CDK complexes in G1 phase phosphorylate retinoblastoma [Rb] proteins, thus releasing E2F transcription factors necessary for cell entry into S-phase [25].

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    Dr Ante Lundberg is a post-doctoral fellow at the Whitehead Institute for Biomedical Research, and a Research Fellow at Harvard Medical School. He received his B.Sc. degree in Biology from Massachusetts Institute of Technology, and his MD degree from Stanford Medical School. He completed his training in Internal Medicine at the Brigham and Women's Hospital, and in Adult Oncology at Dana-Farber Cancer Institute, both in Boston, Massachusetts, U.S.A. The goal of his research is to understand how the cell cycle clock machinery regulates the growth of normal cells, and how alterations within this machinery contribute to the unrestrained growth of cancer.

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    Dr Robert A. Weinberg is a founding member of the Whitehead Institute for Biomedical Research and the Daniel K. Ludwig Professor for Cancer Research at the Massachusetts Institute of Technology. He has been an American Cancer Society Research Professor at Whitehead and MIT since 1985. Dr Weinberg and his colleagues discovered the first human cancer-causing gene, the ras oncogene, and the first known tumour suppressor gene, Rb, the retinoblastoma gene. The principal goal of his research programme is to determine how oncogenes, their normal counterparts (proto-oncogenes), and tumour suppressor genes fit together in the complex circuitry that controls cell growth. He is particularly interested in applying this knowledge to improve the diagnosis and treatment of breast cancer. He is an elected member of the US National Academy of Sciences and Fellow of the American Academy of Arts and Sciences.

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