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Results for “Cell Cycle Checkpoints”

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PubMed1996

Binding of MAR-DNA elements by mutant p53: possible implications for its oncogenic functions.

The tumor suppressor p53 is a multifunctional protein whose main duty is to preserve the integrity of the genome. This function of wild-type p53 as "guardian of the genome" is achieved at different levels, as a cell cycle checkpoint protein, halting the cell cycle upon DNA damage, and via a direct involvement in processes of DNA repair. Alternatively, p53 can induce apoptosis. Mutations in the p53 gene occur in about 50% of all human tumors and eliminate the tumor suppressor functions of p53. However, many mutant p53 proteins have not simply lost tumor suppressor functions but have gained oncogenic properties which contribute to the progression of tumor cells to a more malignant phenotype. The molecular basis for this gain of function of mutant p53 is still unknown. However, mutant (mut) p53 specifically binds to nuclear matrix attachment region (MAR) DNA elements. MAR elements constitute important higher order regulatory elements of chromatin structure and function. By binding to these elements, mut p53 could modulate important cellular processes, like gene expression, replication, and recombination, resulting in phenotypic alterations of the tumor cells. Mut p53 thus could be the first representative of a new class of oncogenes, which exert their functions via long-range alterations or perturbation of chromatin structure and function.

Animals↗

PubMed1997

Inhibition of DNA topoisomerase II alpha gene expression by the p53 tumor suppressor.

DNA topoisomerase II (topo II) is an essential nuclear enzyme involved in major cellular functions such as DNA replication, transcription, recombination, and mitosis. While an elevated level of topo II alpha is associated with cell proliferation, wild-type (wt) p53 inhibits the expression of various growth-stimulatory genes. To determine if p53 downregulates topo II alpha gene expression, a murine cell line, (10)1val, that expresses a temperature-sensitive p53 was utilized. The (10)1val cells had significantly lower levels of topo II alpha mRNA and protein following incubation for 24 h at 32 degrees C (p53 with wt conformation) than at 39 degrees C (p53 with mutant conformation). The effect of p53 on the human topo II alpha gene promoter was determined by using luciferase reporter plasmids containing varying lengths of the topo II alpha promoter transiently cotransfected into p53-deficient (10)1 cells together with wt or mutant p53 expression plasmids. Transcription from the full-length (bp -557 to +90) topo II alpha promoter was decreased 15-fold by wt p53 in a concentration-dependent manner, whereas mutant p53 exerted much weaker inhibition. Consecutive deletion of the five inverted CCAAT elements (ICEs) from the topo II alpha promoter reduced both the basal promoter activity and wt p53-induced suppression. Transcription of the minimal promoter (-32 to +90), which contains no ICE, was slightly stimulated by wt or mutant p53 expression. When point mutations were introduced into the most proximal ICE (-68), the inhibitory effect of wt p53 was alleviated and stimulation of topo II alpha expression resulted. Our study suggests that wt p53 functions as a transcriptional repressor of topo II alpha gene expression, possibly through a functional interaction with specific ICEs. Inactivation of wt p53 may reduce normal regulatory suppression of topo II alpha and contribute to abortive cell cycle checkpoints, accelerated cell proliferation, and alterations in genomic stability associated with neoplasia.

Animals↗

PubMed1995

Ataxia-telangiectasia and cellular responses to DNA damage.

Ataxia-telangiectasia (A-T) is a human disease characterized by high cancer risk, immune defects, radiation sensitivity, and genetic instability. Although A-T homozygotes are rare, the A-T gene may play a role in sporadic breast cancer and other common cancers. Abnormalities of DNA repair, genetic recombination, chromatin structure, and cell cycle checkpoint control have been proposed as the underlying defect in A-T; however, previous models cannot satisfactorily explain the pleiotropic A-T phenotype. Two recent observations help clarify the molecular pathology of A-T: (a) inappropriate p53-mediated apoptosis is the major cause of death in A-T cells irradiated in culture; and (b) ATM, the putative gene for A-T, has extensive homology to several cell cycle checkpoint genes from other organisms. Building on these new observations, a comprehensive model is presented in which the ATM gene plays a crucial role in a signal transduction network that activates multiple cellular functions in response to DNA damage. In this Damage Surveillance Network model, there is no intrinsic defect in the machinery of DNA repair in A-T homozygotes, but their lack of a functional ATM gene results in an inability to: (a) halt at multiple cell cycle checkpoints in response to DNA damage; (b) activate damage-inducible DNA repair; and (c) prevent the triggering of programmed cell death by spontaneous and induced DNA damage. Absence of damage-sensitive cell cycle checkpoints and damage-induced repair disrupts immune gene rearrangements and leads to genetic instability and cancer. Triggering of apoptosis by otherwise nonlethal DNA damage is primarily responsible for the radiation sensitivity of A-T homozygotes and results in an ongoing loss of cells, leading to cerebellar ataxia and neurological deterioration, as well as thymic atrophy, lymphocytopenia, and a paucity of germ cells. Experimental evidence supporting the Damage Surveillance Network model is summarized, followed by a discussion of how defects in the ATM-dependent signal transduction network might account for the A-T phenotype and what insights this new understanding of A-T can offer regarding DNA damage response networks, genomic instability, and cancer.

Apoptosis↗

PubMed1998

Induction of apoptosis in MCF-7:WS8 breast cancer cells by beta-lapachone.

Beta-lapachone (beta-lap) affects a number of enzymes in vitro, including type I topoisomerase (Topo I); however, its exact intracellular target(s) and mechanism of cell killing remain unknown. We compared the cytotoxic responses of MCF-7:WS8 (MCF-7) human breast cancer cells after 4-h pulses of beta-lap or camptothecin (CPT), a known Topo I poison. A direct correlation between loss of survival and apoptosis was seen after beta-lap treatment (LD50 = 2.5 microM). A concentration-dependent, transient sub-2 N preapoptotic cell population was observed at 4-8 h. Estrogen deprivation-induced synchronization and bromodeoxyuridine-labeling studies revealed an apoptotic exit point near the G1-S border. Apoptosis activated by beta-lap was closely correlated with cleavage of lamin B but not with increases in p53/p21 or decreases in bcl-2. Loss of hyperphosphorylated forms of the retinoblastoma protein was observed within 5 h, but cyclins A, B1, and E levels were unaltered for up to 72 h after 5 microM beta-lap. Topo I and Topo IIalpha levels decreased at > 24 h. Logarithmic-phase MCF-7 cells were not affected by < or = 1 microM beta-lap. In contrast, dramatic and irreversible G2-M arrest with no apoptosis was observed in MCF-7 cells treated with 1 microM CPT, monitored for 6-10 days posttreatment. MCF-7 cells treated with supralethal doses of CPT (5 microM) resulted in only approximately 20% apoptosis. No correlation between apoptosis and loss of survival was observed. MCF-7 cells exposed to > 5 microM CPT arrested at key cell cycle checkpoints (i.e., G1, S, and G2-M), with little or no movement for 6 days. Ten-fold increases in p53/p21 and 2-5-fold decreases in bcl-2, Topo I, Topo IIalpha, and cyclins A and B1, with no change in cyclin E, were observed. Temporal decreases in bcl-2 and cleavage of lamin B corresponded to the minimal apoptotic response observed. Beta-lap activated apoptosis without inducing p53/p21 or cell cycle arrest responses and killed MCF-7 cells solely by apoptosis. In contrast, concentration-dependent increases in nuclear p53/p21 and various cell cycle checkpoint arrests were seen in MCF-7 cells after CPT. Despite dramatic p53/p21 protein induction responses, CPT-treated MCF-7 cells showed low levels of apoptosis, possibly due to protective cell cycle checkpoints or the lack of specific CPT-activated apoptotic pathways in MCF-7 cells.

Antineoplastic Agents, Phytogenic↗

PubMed1996

Chemical induction of mitotic checkpoint override in mammalian cells results in aneuploidy following a transient tetraploid state.

Populations of tetraploid cells are found in a variety of human tumours where they may act as precursors of aneuploidy and tumorigenesis. Here we demonstrate the drug induction of tetraploid cells at mitosis by interference with cell cycle checkpoints and the coordination of mitotic events. Tetraploid cells result from mitotic exit in the absence of either chromosome segregation or cytokinesis. One class of agents that induces tetraploidy causes override of cell cycle checkpoints that require metaphase chromosome alignment as a pre-condition for initiating exit from mitosis. As a result cells exposed to such drugs progress partially through mitosis, but exit without chromosome segregation or cytokinesis. Inhibitors of microtubule assembly comprise a second class of agents that induce tetraploidy. Many cell types are incapable of maintaining indefinite mitotic arrest in the presence of microtubule inhibitors and finally exit mitosis without microtubule dependent chromosome segregation. Inhibitors of topoisomerase II represent a third class of drugs that induce tetraploidy at mitosis. By inhibiting DNA decatenation required for sister chromatid separation at the onset of anaphase such drugs block chromosome segregation. When topoisomerase II activity is inhibited, cells nonetheless reform nuclei and exit from mitosis without chromosome segregation. Finally, inhibition of cleavage furrow formation by agents such as cytochalasins represents a fourth mechanism of tetraploidization at mitosis. We find that when Chinese Hamster Ovary cells become tetraploid, regardless of which mechanism induces this state, they are genetically unstable and become aneuploid at the subsequent mitosis. In conclusion, the failure of mitotic checkpoint function can generate gross aneuploidy from which cells with an advantage for tumor growth may be selected.

2-Aminopurine↗

PubMed1998

Mathematical model of the fission yeast cell cycle with checkpoint controls at the G1/S, G2/M and metaphase/anaphase transitions.

All events of the fission yeast cell cycle can be orchestrated by fluctuations of a single cyclin-dependent protein kinase, the Cdc13/Cdc2 heterodimer. The G1/S transition is controlled by interactions of Cdc13/Cdc2 and its stoichiometric inhibitor, Rum1. The G2/M transition is regulated by a kinase-phosphatase pair, Wee1 and Cdc25, which determine the phosphorylation state of the Tyr-15 residue of Cdc2. The meta/anaphase transition is controlled by interactions between Cdc13/Cdc2 and the anaphase promoting complex, which labels Cdc13 subunits for proteolysis. We construct a mathematical model of fission yeast growth and division that encompasses all three crucial checkpoint controls. By numerical simulations we show that the model is consistent with a broad selection of cell cycle mutants, and we predict the phenotypes of several multiple-mutant strains that have not yet been constructed.

Anaphase↗

PubMed1994

Role of retinoblastoma gene product in p53-mediated DNA damage response.

The cellular response to DNA-damaging agents involves the activation of cell cycle checkpoints. Checkpoints provide a transient delay in cell cycle progression, presumably to allow time for the cell to repair the damage. A most important checkpoint, active in the G1 phase of the cell cycle, is mediated by the p53 tumor suppressor gene product. To investigate the role of downstream components of the cell cycle machinery in p53-mediated G1 arrest, the possible involvement of the RB gene product was examined. Rb and p53 proteins were studied by immunoprecipitation and Western blotting experiments in the presence and absence of DNA-damaging treatment. The phosphorylation status of Rb was altered following DNA damage in p53 wild-type cell lines, but was not altered in p53 mutant cell lines, nor in cell lines where p53 function was abrogated by viral gene products. These findings indicate that Rb probably plays a role in the activation of the p53-mediated checkpoint.

Cell Cycle↗

PubMed1996

Genes involved in cell cycle G1 checkpoint control are frequently mutated in human melanoma metastases.

A common characteristic of cancer cells is unrestrained cell division. This may be caused by mutational changes in genes coding for components of cell cycle-controlling networks. Alterations in genes involved in G1 checkpoint control have been registered in many human tumours, and investigations from several laboratories show that such alterations, taken together, are the most frequent changes detected in cancer cells. The present paper describes mutational analysis by polymerase chain reaction-single-strand conformation polymorphism (PCR/SSCP) and nucleotide sequence analysis of the genes coding for the p15, p53 and N-ras proteins in 26 metastases from 25 melanoma patients. The registered mutation frequencies add together with previously registered mutations in p16 in the same patient samples to a substantial total frequency of 44% of patients with mutation in at least one of the investigated genes. These results show the occurrence of heterogeneous defects among components of the cell cycle controlling machinery in a human melanoma tumour sample collection and demonstrate that the total frequency of detected alterations increases with the number of cell cycle controlling genes included in the screening panel.

Carrier Proteins↗

PubMed1996

Requirement for Ku80 in growth and immunoglobulin V(D)J recombination.

The DNA-dependent protein kinase (DNA-PK) is a mammalian serine/threonine kinase that is implicated in the repair of DNA double-strand breaks, DNA replication, transcription, and V(D)J recombination. To determine the role of the DNA-binding subunit of DNA-PK in vivo, we targeted Ku80 in mice. In mutant mice, T and B lymphocyte development is arrested at early progenitor stages and there is a profound deficiency in V(D)J rearrangement. Although Ku80-/- mice are viable and reproduce, they are 40-60% of the size of littermate controls. Consistent with this growth defect, fibroblasts derived from Ku80-/- embryos showed an early loss of proliferating cells, a prolonged doubling time, and intact cell-cycle checkpoints that prevented cells with damaged DNA from entering the cell-cycle. The unexpected growth phenotype suggests a new and important link between Ku80 and growth control.

Animals↗

PubMed1998

Chromosomal instability is correlated with telomere erosion and inactivation of G2 checkpoint function in human fibroblasts expressing human papillomavirus type 16 E6 oncoprotein.

Cell cycle checkpoints and tumor suppressor gene functions appear to be required for the maintenance of a stable genome in proliferating cells. In this study chromosomal destabilization was monitored in relation to telomere structure, lifespan control and G2 checkpoint function. Replicative senescence was inactivated in secondary cultures of human skin fibroblasts by expressing the human papillomavirus type 16 (HPV-16) E6 oncoprotein to inactivate p53. Chromosome aberrations were enumerated during in vitro aging of isogenic control (F5neo) and HPV-16E6-expressing (F5E6) fibroblasts. We found that structural and numerical aberrations in chromosomes were significantly increased in F5E6 cells during aging in vitro and fluorescence in situ hybridization (FISH) analysis using chromosome-specific probes demonstrated the occurrence of rearrangements involving chromosome 4 and 6 in genetically unstable F5E6 cells. Flow cytometry and karyotypic analyses revealed increased polyploidy and aneuploidy in F5E6 cells only at passages > 16, although these cells displayed defective mitotic spindle checkpoint function associated with inactivation of p53 at passages 5 and 16. G2 checkpoint function was confirmed to be gradually but progressively inactivated during in vitro aging of E6-expressing cells. Aging of F5neo fibroblasts was documented during in vitro passaging by induction of a senescence-associated marker, pH 6.0 lysosomal beta-galactosidase. F5E6 cells displayed extension of in vitro lifespan and did not induce beta-galactosidase at high passage. Erosion of telomeres during in vitro aging of telomerase-negative F5neo cells was demonstrated by Southern hybridization and by quantitative FISH analysis on an individual cell level. Telomeric signals diminished continuously as F5neo cells aged in vitro being reduced by 80% near the time of replicative senescence. Telomeric signals detected by FISH also decreased continuously during aging of telomerase-negative F5E6 cells, but telomeres appeared to be stabilized at passage 34 when telomerase was expressed. Chromosomal instability in E6-expressing cells was correlated (P < 0.05) with both loss of telomeric signals and inactivation of G2 checkpoint function. The results suggest that chromosomal stability depends upon a complex interaction among the systems of telomere length maintenance and cell cycle checkpoints.

Cell Line↗

PubMed1998

Attenuation of G1 checkpoint function by the non-genotoxic carcinogen phenobarbital.

Non-genotoxic chemical carcinogens are capable of inducing tumors in rodents without interacting with or directly altering the genetic material. Since a preponderance of evidence suggests that cancer results from the accumulation of genetic alterations, the mechanisms by which many non-genotoxic carcinogens induce genotoxic events remain unclear. The present study investigated whether the mitogenic, non-genotoxic carcinogen phenobarbital (PB) could alter cell-cycle checkpoint controls, thereby indirectly leading to the accumulation of genetic damage. Initial studies involved characterizing cell-cycle checkpoint responses to DNA damage in freshly isolated B6C3F1 mouse hepatocytes. These cells responded to bleomycin-induced DNA damage by arresting in G1 and G2. Cell-cycle arrest was coupled with p53 protein induction; however, p21WAF1 protein levels remained unchanged. Studies that utilized hepatocytes isolated from C57BL p53-/- mice showed that the DNA damage-induced G1 cell-cycle arrest was dependent on p53 function, but cell-cycle arrest in G2 was not affected by loss of p53. PB was able to delay and attenuate the G1 checkpoint response without altering G2 checkpoint function. A reduction in p53 protein, but not transcript levels, was observed in hepatocytes exposed to PB. Additionally, PB delayed and attenuated p53 protein induction during DNA damage, which suggests that changes in the p53 protein may be contributing to the attenuated G1 checkpoint response caused by PB. Altered G1 checkpoint function represents an epigenetic mechanism by which phenobarbital may prevent the detection and repair of DNA damage and indirectly increase the frequency of genotoxic events above that occurring spontaneously. Abrogation of checkpoint controls may, thus, play an important mechanistic role in mitogenic, non-genotoxic chemical carcinogenesis.

Animals↗

PubMed2000

Involvement of apoptosis in mitomycin C hypersensitivity of Chinese hamster cell mutants.

To elucidate the mechanisms of the mammalian cell defense against cross-linking agents, we studied previously cellular responses to mitomycin C (MMC) treatment in two MMC-hypersensitive hamster cell mutants' V-H4 and V-C8, as well as their parental cell line V79. In the present report, we investigated whether alterations in cell cycle checkpoints and induction of apoptosis could be responsible for the MMC hypersensitivity of the V-H4 and V-C8 mutant cell lines. First, we found that parental and mutant cells exhibited similar cell cycle responses to MMC concentrations of equivalent cytotoxicity, arguing against a defective cell cycle checkpoint in hypersensitive cell lines. In contrast, we showed that mutant cells underwent greater levels of apoptosis following MMC treatment than parental cells. These findings indicate that increased induction of apoptosis contributes to the hypersensitivity of V-H4 and V-C8 cells to the growth inhibitory effect of MMC. This differential apoptotic response was observed with both equimolar and equitoxic MMC doses and was specific to the cross-linking agent MMC, suggesting that control of the apoptotic process is altered in both MMC-hypersensitive mutants. The defective genes in V-H4 and V-C8 cells would then function in the regulation of an apoptotic pathway triggered by MMC-induced damage and independent of p53-mediated transcription.

Animals↗

PubMed1996

Spontaneous p53 mutation in murine mesothelial cells: increased sensitivity to DNA damage induced by asbestos and ionizing radiation.

The p53 gene regulates the G1 cell cycle checkpoint in response to DNA damage. A primary murine mesothelial cell line (D9) spontaneously acquired a point mutation at codon 135 in exon 5 of the p53 gene, resulting in substitution of alanine for proline; early passage D9 cells expressed wild-type p53. The growth rate of late passage D9 cells that acquired the p53 mutation was increased compared to that of early passage cells; however, this mutation was not sufficient to confer tumorigenicity to this cell line. Mammalian cells that express wild-type p53 show a transient arrest in G1 after exposure to ionizing radiation. Early passage D9 cells showed a G1 arrest following ionizing radiation, while late passage D9 cells arrested in G2 or mitosis. The clastogenic effects of ionizing radiation can be demonstrated by the cytokinesis-arrested micronucleus assay. Following treatment with cytochalasin B to arrest cytokinesis, ionizing radiation induced micronuclei in 50% of late passage D9 cells compared to 15% of early passage cells. After exposure to 15 micrograms/cm2 of crocidolite asbestos fibers, 18% of late passage cells had micronuclei compared to 4% of early passage cells. It is hypothesized that loss of the G1 cell cycle checkpoint contributes to genetic instability in murine mesothelial cells.

Animals↗

PubMed1994

Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status.

It has been convincingly demonstrated that genotoxic stresses cause the accumulation of the tumor suppressor gene p53. One important consequence of increased p53 protein levels in response to DNA damage is the activation of a G1-phase cell cycle checkpoint. It has also been shown that G1-phase cell cycle checkpoints are activated in response to other stresses, such as lack of oxygen. Here we show that hypoxia and heat, agents that induce cellular stress primarily by inhibiting oxygen-dependent metabolism and denaturing proteins, respectively, also cause an increase in p53 protein levels. The p53 protein induced by heat is localized in the cytoplasm and forms a complex with the heat shock protein hsc70. The increase in nuclear p53 protein levels and DNA-binding activity and the induction of reporter gene constructs containing p53 binding sites following hypoxia occur in cells that are wild type for p53 but not in cells that possess mutant p53. However, unlike ionizing radiation, the accumulation of cells in G1 phase by hypoxia is not strictly dependent on wild-type p53 function. In addition, cells expressing the human papillomavirus E6 gene, which show increased degradation of p53 by ubiquitination and fail to accumulate p53 in response to DNA-damaging agents, do increase their p53 levels following heat and hypoxia. These results suggest that hypoxia is an example of a "nongenotoxic" stress which induces p53 activity by a different pathway than DNA-damaging agents.

Animals↗

PubMed1995

Cell cycle and apoptosis: common pathways to life and death.

Programmed cell death, or apoptosis, is a highly regulated process used to eliminate unwanted or damaged cells from multicellular organisms. The morphology of cells undergoing apoptosis is similar to cells undergoing both normal mitosis and an aberrant form of mitosis called mitotic catastrophe. During each of these processes, cells release substrate attachments, lose cell volume, condense their chromatin, and disassemble the nuclear lamina. The morphological similarities among cells undergoing these processes suggest that the underlying biochemical changes also may be related. The susceptibility of cells to apoptosis frequently depends on the differentiation state of the cell. Additionally, cell cycle checkpoints appear to link the cell cycle to apoptosis. Deregulation of the cell cycle components has been shown to induce mitotic catastrophe and also may be involved in triggering apoptosis. Some apoptotic cells express abnormal levels of cell cycle proteins and often contain active Cdc2, the primary kinase active during mitosis. Although cell cycle components may not be involved in all forms of apoptosis, in many instances cell proliferation and cell death may share common pathways.

Animals↗

PubMed1999

Gamma-rays-induced death of human cells carrying mutations of BRCA1 or BRCA2.

There is now evidence to suggest that BRCA1 and BRCA2 are involved in the response of cells to DNA damage and cell cycle checkpoint control. This report examines the death pathways of human cells with various BRCA1 and BRCA2 genotypes after exposure to gamma-rays. A lack of functional BRCA1 and BRCA2 led to defective repair of DNA double-strand breaks in irradiated cells. This impairment resulted in a relaxation of cell cycle checkpoints, production of micronuclei, and a loss of proliferative capacity. Heterozygous BRCA1 and BRCA2 mutations also led to enhanced radiosensitivity, with an impaired proliferative capacity after irradiation. The existence of a phenotype related to radiosensitivity in BRCA1+/- and BRCA2+/- cells raises the question of the response of heterozygous women to radiation.

BRCA1 Protein↗

PubMed2000

The controlling role of ATM in homologous recombinational repair of DNA damage.

The human genetic disorder ataxia telangiectasia (A-T), caused by mutation in the ATM gene, is characterized by chromosomal instability, radiosensitivity and defective cell cycle checkpoint activation. DNA double-strand breaks (dsbs) persist in A-T cells after irradiation, but the underlying defect is unclear. To investigate ATM's interactions with dsb repair pathways, we disrupted ATM along with other genes involved in the principal, complementary dsb repair pathways of homologous recombination (HR) or non-homologous end-joining (NHEJ) in chicken DT40 cells. ATM(-/-) cells show altered kinetics of radiation-induced Rad51 and Rad54 focus formation. Ku70-deficient (NHEJ(-)) ATM(-/-) chicken DT40 cells show radiosensitivity and high radiation-induced chromosomal aberration frequencies, while Rad54-defective (HR(-)) ATM(-/-) cells show only slightly elevated aberration levels after irradiation, placing ATM and HR on the same pathway. These results reveal that ATM defects impair HR-mediated dsb repair and may link cell cycle checkpoints to HR activation.

Animals↗

PubMed1997

The role of ErbB-2 tyrosine kinase receptor in cellular intrinsic chemoresistance: mechanisms and implications.

The erbB family of tyrosine kinase receptors is involved in the regulation of a variety of vital functions including cell proliferation, cell differentiation, and stress response. Alteration in the expression of erbB receptors occurs in numerous tumor types and plays an important role in cancer development, cancer progression, and susceptibility to cell killing by anticancer agents. Of particular interest is the intrinsic drug resistance associated with overexpression of the erbB-2 receptor. In general, tumor cells overexpressing erbB-2 are intrinsically resistant to DNA-damaging agents such as cisplatin. While the molecular mechanisms by which erbB-2 induces drug resistance are not yet established, there is evidence that this may be a consequence of altered cell cycle checkpoint and DNA repair mechanisms and dysregulation of apoptotic pathway(s). The apoptotic signal induced by many anticancer drugs originates at a receptor on the cell membrane and is transduced through a signaling cascade to the nucleus. Drug-induced apoptosis is dependent on the balance between cell cycle checkpoints and DNA repair mechanisms. Blockade of erbB-2 signaling using erbB-2 antagonists, dominant negative mutants, or chemical inhibitors of erbB-2 tyrosine kinase activity induces cell cycle arrest, inhibits DNA repair, and (or) promotes apoptosis. Less understood are downstream signal transduction cascades by which erbB-2 affects these regulatory mechanisms. The diversity of erbB receptors results in an interconnected network of cell signaling pathways that determine tumor cell fate in response to chemotherapy stress. Further investigations on the role of erbB-coupled signaling in the regulation of stress responsive genes are critical to understand the mechanisms by which tumor cells escape cell death, and will contribute to the development of alternative therapeutic targets to overcome intrinsic drug resistance in clinical settings.

Animals↗