Protein kinase A and chromosomal stability.
01 Jun 2002-Annals of the New York Academy of Sciences (Blackwell Publishing Ltd)-Vol. 968, Iss: 1, pp 148-157
TL;DR: This review will discuss the potential participation of cAMP‐dependent protein kinase A in chromosomal stability, which includes the association of PKA with the centrosome, microtubules, and the anaphase‐promoting complex/cyclosome (ACP/C), all key aspects of proper chromosomal segregation.
Abstract: All malignant human tumors contain chromosomal rearrangements. Among them, the majority of solid tumors show chromosomal instability, caused by aberrations in chromosomal segregation during cell division. Chromosomal instability, defined as increased probability of formation of novel chromosomal mutations compared to that of normal or control cells, appears to be a feature of tumorigenesis in vivo and in vitro (in cancer cell lines). Several enzymatic kinases are involved in maintaining proper chromosomal segregation and regulating cell cycle progression. One such kinase, cAMP-dependent protein kinase A (PKA), has a functional role in many aspects of cell signaling, metabolism, and proliferation. In this review, we will discuss the potential participation of PKA in chromosomal stability. This role includes the association of PKA with the centrosome, microtubules, and the anaphase-promoting complex/cyclosome (ACP/C), all key aspects of proper chromosomal segregation.
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TL;DR: CNC is the first human disease caused by mutations of one of the subunits of the PKA holoenzyme, a critical component of numerous cellular signaling systems, and has wide implications for cAMP involvement in endocrine tumorigenesis.
Abstract: Carney complex (CNC) is a unique multiple endocrine neoplasia syndrome (MIM 160980) which is characterized by unusual biochemical features (chronic hypersomatotropinemia and paradoxical responses of c
91 citations
TL;DR: Hereditary origin of a tumor helps toward early discovery of its mutated gene; for example, it supports the compilation of a DNA panel from index cases to identify that gene by finding mutations in it.
Abstract: Hereditary origin of a tumor helps toward early discovery of its mutated gene; for example, it supports the compilation of a DNA panel from index cases to identify that gene by finding mutations in it. The gene for a hereditary tumor may contribute also to common tumors. For some syndromes, such as hereditary paraganglioma, several genes can cause a similar syndrome. For other syndromes, such as multiple endocrine neoplasia 2, one gene supports variants of a syndrome. Onset usually begins earlier and in more locations with hereditary than sporadic tumors. Mono- or oligoclonal ("clonal") tumor usually implies a postnatal delay, albeit less delay than for sporadic tumor, to onset and potential for cancer. Hormone excess from a polyclonal tissue shows onset at birth and no benefit from subtotal ablation of the secreting organ. Genes can cause neoplasms through stepwise loss of function, gain of function, or combinations of these. Polyclonal hormonal excess reflects abnormal gene dosage or effect, such as activation or haploinsufficiency. Polyclonal hyperplasia can cause the main endpoint of clinical expression in some syndromes or can be a precursor to clonal progression in others. Gene discovery is usually the first step toward clarifying the molecule and pathway mutated in a syndrome. Most mutated pathways in hormone excess states are only partly understood. The bases for tissue specificity of hormone excess syndromes are usually uncertain. In a few syndromes, tissue selectivity arises from mutation in the open reading frame of a regulatory gene (CASR, TSHR) with selective expression driven by its promoter. Polyclonal excess of a hormone is usually from a defect in the sensor system for an extracellular ligand (e.g., calcium, glucose, TSH). The final connections of any of these polyclonal or clonal pathways to hormone secretion have not been identified. In many cases, monoclonal proliferation causes hormone excess, probably as a secondary consequence of accumulation of cells with coincidental hormone-secretory ability.
86 citations
TL;DR: Although the authors have begun to tap into the mechanisms behind Boveri's initial observation that supernumerary centrosomes cause chromosome missegregation in sea urchin eggs, there is still much left to discover with regard to chromosome instability in cancer.
Abstract: Although we have begun to tap into the mechanisms behind Boveri's initial observation that supernumerary centrosomes cause chromosome missegregation in sea urchin eggs, there is still much left to discover with regard to chromosomal instability in cancer. Many of the molecular players involved in regulation of the centrosome and cell cycles, and the coupling of the two cycles to produce a bipolar mitotic spindle have been identified. One theme that has become apparent is that cross talk and interrelatedness of the pathways serve to provide redundant mechanisms to maintain genomic integrity. In spite of this, cells occasionally fall prey to insults that initiate and maintain the chromosomal instability that results in viable malignant tumours. Deregulation of centrosome structure is an integral aspect of the origin of chromosomal instability in many cancers. There are numerous routes to centrosome amplification including: environmental insults such as ionising radiation and exposure to estrogen (Li et al., 2005); failure of cytokinesis; and activating mutations in key regulators of centrosome structure and function. There are two models for initiation of centrosome amplification (Figure 2). In the first, centrosome duplication and chromosome replication remain coupled and cells enter G2 with 4N chromosomes and duplicated centrosomes. However, these cells may fail to complete mitosis, and thus reenter G1 as tetraploid cells with amplified centrosomes. In the second, the centrosome cycle is uncoupled from chromosome replication and cells go through one or more rounds of centriole/centrosome duplication in the absence of chromosome replication. If these cells then go through chromosome replication accompanied by another round of centrosome duplication, cells complete G2 with 4N chromosomes and more than 2 centrosomes, and therefore are predisposed to generate multipolar mitotic spindles. Fragmentation of centrosomes due to ionising radiation is a variation of the second model. Once centrosome amplification is present, even in a diploid cell, that cell has the potential to yield viable aneuploid progeny. The telophase cell in Figure 3C illustrates this scenario. In a normal telophase configuration, the total number of chromosomes is 92 (resulting from the segregation of 46 pairs of chromatids), with each daughter nucleus containing 46 individual chromosomes. Based on the number of kinetochore signals present, the lower nucleus in Figure 3C has approximately 28 chromosomes, and the elongate upper nucleus has approximately 60, for a total of 88. Due to superimposition of kinetochores in this maximum projection image, 88 is an underestimate of the actual number of kinetochores and is not significantly different from the expected total of 92. A cell resulting from the lower nucleus with only around 28 chromosomes would probably not be viable, much as Boveri's experiments indicated. However, the upper nucleus with at least 60 chromosomes could be viable. This cell would enter G1 as hypotriploid (69 chromosomes = triploid) with 2 centrosomes. During S and G2, the centrosomes and chromosomes would double, and the following mitosis could be tetrapolar with a 6N chromosome content. When centrosome amplification is accompanied by permissive lapses in cell cycle checkpoints, the potential for malignant growth is present. These lapses could result from specific genetic mutations and amplifications, epigenetic gene silencing, or from massive chromosomal instability caused by the centrosome amplification. Centrosome amplification, therefore, can serve to exacerbate and/or generate genetic instabilities associated with cancers.
73 citations
Cites background from "Protein kinase A and chromosomal st..."
...In cultured cells, inactivation of Plk2 interferes with centriole re-duplication, implicating Plk2 kinase activity in regulating this process (Warnke et al., 2004)....
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...Key cell cycle regulators described at the centrosome include: p53, the cyclin/cdks, protein kinase A (PKA), Aurora-A, Plk1, BRCA1 and BRCA2, and the anaphase promoting complex (APC/cyclosome) (Bailly et al., 1992; DeCamilli et al., 1986; Diviani et al., 2000; Fry et al., 2000; Giannakakou et al., 2000; Hsu and White, 1998; Keryer et al., 2003; Kraft et al., 2003; Matsumoto and Maller, 2004; Matyakhina et al., 2002; Nigg et al., 1986; Pockwinse et al., 1997; Rattner et al., 1990; Tugendreich et al., 1995; Xu et al., 1999)....
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...…1986; Diviani et al., 2000; Fry et al., 2000; Giannakakou et al., 2000; Hsu and White, 1998; Keryer et al., 2003; Kraft et al., 2003; Matsumoto and Maller, 2004; Matyakhina et al., 2002; Nigg et al., 1986; Pockwinse et al., 1997; Rattner et al., 1990; Tugendreich et al., 1995; Xu et al., 1999)....
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...Plk2 is activated near the G1/S transition of the cell cycle, but its activity is not required for centrosome localisation (Warnke et al., 2004)....
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...Finally, centrosome behaviour, particularly at the time of mitosis, operates under the control of several centrosome-associated kinases, including protein kinase A (PKA), Aurora A, Nek2, and the Polo-like kinases Plk1 and Plk2 (Casenghi et al., 2003; Chen et al., 2003; DeCamilli et al., 1986; Fry, 2002; Fry et al., 1998b; Giet et al., 1999; Hamill et al., 2002; Kraft et al., 2003; Logarinho and Sunkel, 1998; Lou et al., 2004; Matyakhina et al., 2002; Meraldi and Nigg, 2001; Nigg et al., 1985; Tsvetkov et al., 2003; Yanai et al., 1997)....
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TL;DR: Control of cell cycle progression relies on unique regulation of centrosomal cAMP/PKA signals through PKA and PDE4D3 interaction with the A kinase anchoring protein AKAP9.
Abstract: Previous work has shown that the protein kinase A (PKA)–regulated phosphodiesterase (PDE) 4D3 binds to A kinase–anchoring proteins (AKAPs). One such protein, AKAP9, localizes to the centrosome. In this paper, we investigate whether a PKA–PDE4D3–AKAP9 complex can generate spatial compartmentalization of cyclic adenosine monophosphate (cAMP) signaling at the centrosome. Real-time imaging of fluorescence resonance energy transfer reporters shows that centrosomal PDE4D3 modulated a dynamic microdomain within which cAMP concentration selectively changed over the cell cycle. AKAP9-anchored, centrosomal PKA showed a reduced activation threshold as a consequence of increased autophosphorylation of its regulatory subunit at S114. Finally, disruption of the centrosomal cAMP microdomain by local displacement of PDE4D3 impaired cell cycle progression as a result of accumulation of cells in prophase. Our findings describe a novel mechanism of PKA activity regulation that relies on binding to AKAPs and consequent modulation of the enzyme activation threshold rather than on overall changes in cAMP levels. Further, we provide for the first time direct evidence that control of cell cycle progression relies on unique regulation of centrosomal cAMP/PKA signals.
72 citations
Cites background from "Protein kinase A and chromosomal st..."
...…of cell cycle regulation, including centrosome duplication, S phase, G2 arrest, mitotic spindle formation, exit from M phase, and cytokinesis (Matyakhina et al., 2002); however, which, if any, of these functions is regulated by a PKA subset targeted at the centrosome remains to be…...
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...ing centrosome duplication, S phase, G2 arrest, mitotic spindle formation, exit from M phase, and cytokinesis (Matyakhina et al., 2002), and it is possible that different cAMP/PKA signaling...
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...PKA has been shown to be involved in many aspects of cell cycle regulation, including centrosome duplication, S phase, G2 arrest, mitotic spindle formation, exit from M phase, and cytokinesis (Matyakhina et al., 2002); however, which, if any, of these functions is regulated by a PKA subset targeted at the centrosome remains to be established....
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...…of cell cycle regulation, including centrosome duplication, S phase, G2 arrest, mitotic spindle formation, exit from M phase, and cytokinesis (Matyakhina et al., 2002), and it is possible that different cAMP/PKA signaling modules may be responsible for the regulation of specific cell…...
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TL;DR: Logistic analysis revealed that the disease (cancer) is the only factor contributing to the elevation of ECPKA activity in cancer patients and can be used in cancer detection and for monitoring response to therapy with other screening or diagnostic techniques.
Abstract: The overexpression of cyclic AMP (cAMP)-dependent protein kinase (PKA) has been reported in patients with cancer, and PKA inhibitors have been tested in clinical trials as a novel cancer therapy. The present study was designed to characterize the population distribution of extracellular activity of cAMP-dependent protein kinase (ECPKA) and its potential value as a biomarker for cancer detection and monitoring of cancer therapy. The population distribution of ECPKA activity was determined in serum samples from a Chinese population consisting of a total of 603 subjects (374 normal healthy volunteers and 229 cancer patients). The serum ECPKA was determined by a validated sensitive radioassay, and its diagnostic values (including positive and negative predictive values) were analyzed. The majority of normal subjects (>70%) have undetectable or very low levels of serum ECPKA. In contrast, the majority of cancer patients (>85%) have high levels of ECPKA. The mean ECPKA activity in the sera of cancer patients was 10.98 units/mL, 5-fold higher than that of the healthy controls (2.15 units/mL; P < 0.001). In both normal subjects and cancer patients, gender and age had no significant influence on the serum ECPKA. Among factors considered, logistic analysis revealed that the disease (cancer) is the only factor contributing to the elevation of ECPKA activity in cancer patients. In conclusion, ECPKA may function as a cancer marker for various human cancers and can be used in cancer detection and for monitoring response to therapy with other screening or diagnostic techniques.
57 citations
Cites background from "Protein kinase A and chromosomal st..."
...More importantly, PKA has been implicated in the initiation and progression of numerous cancers and in response to cancer therapy (3-7)....
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References
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TL;DR: Each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment, which should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.
Abstract: It is proposed that most neoplasms arise from a single cell of origin, and tumor progression results from acquired genetic variability within the original clone allowing sequential selection of more aggressive sublines. Tumor cell populations are apparently more genetically unstable than normal cells, perhaps from activation of specific gene loci in the neoplasm, continued presence of carcinogen, or even nutritional deficiencies within the tumor. The acquired genetic insta0ility and associated selection process, most readily recognized cytogenetically, results in advanced human malignancies being highly individual karyotypically and biologically. Hence, each patient's cancer may require individual specific therapy, and even this may be thwarted by emergence of a genetically variant subline resistant to the treatment. More research should be directed toward understanding and controlling the evolutionary process in tumors before it reaches the late stage usually seen in clinical cancer.
6,179 citations
TL;DR: There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels, and recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
Abstract: Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.
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TL;DR: This review describes progress toward understanding the mechanism of dynamic instability of pure tubulin and discusses the function and regulation of microtubule dynamic instability in living cells.
Abstract: The polymerization dynamics of microtubules are central to their biological functions. Polymerization dynamics allow microtubules to adopt spatial arrangements that can change rapidly in response to cellular needs and, in some cases, to perform mechanical work. Microtubules utilize the energy of GTP hydrolysis to fuel a unique polymerization mechanism termed dynamic instability. In this review, we first describe progress toward understanding the mechanism of dynamic instability of pure tubulin and then discuss the function and regulation of microtubule dynamic instability in living cells.
2,484 citations
01 Jan 1992
TL;DR: The results suggest that chromosomes with short (TTAGGG)n tracts are recombinogenic, critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization.
Abstract: Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer. Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination, we have measured telomere length, telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5. In all mortal populations, telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures. When transformed cells reached crisis, the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed. In immortal cells, telomere length and frequency of dicentric chromosomes stabilized after crisis. Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations. These results suggest that chromosomes with short (TTAGGG)n tracts are recombinogenic, critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization.
2,014 citations
TL;DR: In this article, the authors measured telomere length, telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5 and found that telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures.
Abstract: Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer. Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination, we have measured telomere length, telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5. In all mortal populations, telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures. When transformed cells reached crisis, the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed. In immortal cells, telomere length and frequency of dicentric chromosomes stabilized after crisis. Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations. These results suggest that chromosomes with short (TTAGGG)n tracts are recombinogenic, critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization.
1,987 citations