M

Figure 1 Molecular mechanisms governing the cell cycle. Symbols: + and - symbols represents the effects on the activity of the targeted protein as well as transcriptional regulation; P represent a phosphorylation event; ? represent a probable effect, but not fully demonstrated. DHFR, dihydrofolate reductase; TK, thymidine kinase; TS, thymidilate synthase; POL, DNA polymerase-a.

loss of Rb function through permanent hyperphosphorylation, leading to accumulation of active E2F factors. This can occur by deregulated expression of cyclin D or CDK4, as a result of amplification or translocation of the respective genes. For example, CDK4 is amplified in gliomas and sarcomas.87 Alternatively, point mutations abrogating p16Ink4a binding have also been identified in CDK4. Third, CKI genes such as the INK4 gene are often deleted or silenced by hypermethylation of the gene promoter90 in human tumors.

Key observations made in different biological systems have also identified Rb as an important player in cell fate determination (i.e., the differentiation process), by inducing apoptosis. This can be accomplished by two different mechanisms: (1) through regulation of apoptosis either in a E2F1, p19 (the sixth and last product of the INK4A/ ARF locus) and p53-dependent fashion,91,91-95 or (2) in a E2F1-independent manner, through c-Jun N-terminal kinase (JNK), nuclear c-Abl, and p84N5.96-100 Because for a cell to become tumorigenic, it has to turn out to be resistant to apoptosis (see Section 7.01.5.3) and acquire properties leading to a strong blockade of the cell death machinery.

7.01.5.1.2 The G2/M transition, control of deoxyribonucleic acid (DNA) damage, and the spindle checkpoint

Historically identified as mitosis promoting factor (MPF), the Cdk1/cyclin B complex is the key element responsible for the onset of mitosis.101 Regulation of the activity of this complex is performed at multiple levels. First, the cyclin B protein is expressed uniquely at the end of the S phase and during the M phase, being rapidly degraded as cells enter the next G1 phase.102 Second, Cdk1 (also known as Cdc2) kinase activity is tightly regulated by an antagonistic posttranslation modification: phosphorylation by the Wee1 and myt1 kinases103 and dephosphorylation by the Cdc25B/ C phosphatases.104 Phosphorylated Cdk1 is kept inactive during the G2 phase and its dephosphorylation is in fact the rate-limiting step for entry into mitosis.105 Finally, because the primary sequence of cyclin B contains a nuclear exclusion signal, the dephosphorylated and active Cdk1/cyclinB complex is actively exported from the nucleus into the cytosol until the beginning of prophase.106 Similarly, Cdc25C is also regulated by proteolysis and nuclear exclusion.107 Exact duplication of the DNA during the S phase dictates the entry of the dividing cells into the M phase. The DNA contained in every mammalian cells is under constant attack by agents (e.g., UV radiation or chemicals) that can either break the phosphodiester bonds on the backbone of the DNA helix or damage its bases. Defects in the repair of double-strand breaks can lead to chromosomal instability, a phenomenon intrinsically linked to carcinogenesis,108 as all malignant tumor types have been shown to contain chromosomal aberrations.109 Different mechanisms are required to repair the DNA damages or mismatches and the challenge to fix the problems can vary in the different phases of the cell cycle (Figure 2). Halting or slowing DNA replication until the error or damage has been repaired limits heritable mutations in daughter cells and controls the viability of the damaged cells. Initiation of the activity of ATR and ATM, which are members of the (phosphatidylinositol-3-OH kinase)-like kinase (PIKK) family, is the first step in the DNA damage/repair pathways that inhibit cell cycle progression.110 ATR kinase seems to be critical for DNA damages located in DNA being replicated (leading to replication fork arrest) whereas ATM seems to be primarily activated following

Figure 2 DNA damage and cell cycle checkpoints. This representative scheme shows the activity of the proteins involved in the DNA damage response and the final output on cell cycle.

Output on cell cycle

G1 and G2 phase arrest

S phase arrest

Figure 2 DNA damage and cell cycle checkpoints. This representative scheme shows the activity of the proteins involved in the DNA damage response and the final output on cell cycle.

DNA damage in nonreplicating DNA.111 ATR and ATM work closely with the downstream transducer kinases Chk1 and Chk2, and the members of the polo-like kinases family (Plks) to control cell progression and the cellular responses to DNA repair, transcription, chromatin assembly, and cell death.

As described above, the DNA repair and cell cycle checkpoint pathways facilitate cellular responses to endogenous and exogenous sources of DNA damage, and it is reasonable to assume that alterations in these pathways increase the risk of cancer developing by permitting the survival or the continued growth of cells with genomic abnormalities. The dysfunction of some of the components of these pathway in cancer cells is briefly discussed in the following paragraphs.

The TP53 tumor suppressor gene encodes the p53 protein, also called the guardian of the human genome. This protein is activated upon DNA damage112 leading to G1 cell cycle arrest113,114 and eventually to apoptosis.115 It can also affect the G2/M transition through cyclin B downregulation, or disruption of the Cdk1/Cyclin B complex.116 TP53 is found mutated in around 50% of all human cancers,117 and the p53 inhibitory partner Mdm2, which targets p53 for degradation by the ubiquitin/proteasome pathway, is amplified in 10-20% of bone and soft tissue tumors.118 Mice carrying a heterozygous deletion of TP53 are highly prone to spontaneous tumor development. Individuals with the Li-Fraumeni syndrome, carrying a germline deletion of only one p53 allele, are highly susceptible to cancer development. 119 This underlines the critical role of p53 as a tumor suppressor.

Although the ATM gene is not considered to be a tumor suppressor gene, its loss of function is frequently observed in patients with ataxia telangiectasia, a tumor-prone neurodegenerative disorder.120 Moreover, somatic mutations in ATM have been identified in some sporadic cancers, particularly leukemia.121 Typical cytogenetic changes seen in tumors from individuals with ataxia telangiectasia often involve aberrant oncogenic rearrangements at the T cell receptor loci,122 underlining a link between normal DNA damage repair (the immunoglobulin-gene recombination) and the physiological function of the ATM protein.123

Chk2 is a stable protein expressed at constant levels throughout the cell cycle, but aberrant low levels of Chk2 have been found in subsets of human breast carcinomas, testicular tumors, and lymphomas. Furthermore, germline mutations in the Chk2 gene have been identified in some Li-Fraumeni syndrome patients with the wild-type p53 allele.124

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