Regulation and regulatory activities of centrosomes

Whitehead, Clark M.; Salisbury, Jeffrey L.

doi:10.1002/(sici)1097-4644(1999)75:32+<192::aid-jcb23>3.0.co;2-5

Cited by 17 publications

(7 citation statements)

References 34 publications

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“…Centrosome duplication and microtubule nucleation activity are precisely regulated during development and the cell cycle, and irregularities in this process could lead to abnormal cell divisions 19, 20. We have provided evidence for an interaction of ELAC2 with the γ‐tubulin complex.…”

Section: Discussionmentioning

confidence: 71%

The product of the candidate prostate cancer susceptibility gene ELAC2 interacts with the γ‐tubulin complex

Korver¹,

Guevara²,

Chen

et al. 2003

Intl Journal of Cancer

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Despite its high incidence and mortality rate, the molecular mechanisms underlying the oncogenesis and progression of prostate cancer are poorly understood. Recent studies suggest that hereditary prostate cancer is a complex disease involving multiple susceptibility genes, different models of Mendelian inheritance, incomplete penetrance and varying population ethnicity frequencies. 1,2 Recently a novel candidate susceptibility gene, ELAC2 (HPC2), was identified on chromosome 17p. 3 Two pedigree-specific high-risk variants, 1641insG and Arg781His, and 2 common moderate-risk variants, Ser217Leu and Ala541Thr, were identified. The results on ELAC2 mutations presented in the literature so far are not always consistent with a major role for ELAC2 as a prostate cancer susceptibility gene. 4 -6 However, association of the common missense variants in ELAC2 with sporadic prostate patients has been described in several independent studies. 5,[7][8][9] The ELAC2 gene encodes a protein of 826 amino acids and is a member of an uncharacterized, conserved gene family; orthologs have been identified in bacteria, S. cerevisiae, S. pombe and C. elegans. 3 Alignment of the sequences revealed a conserved histidine-motif, reminiscent of the one found in metallo-beta-lactamases. A recently published study on the ElaC gene product from E. Coli identifies it as a binuclear zinc phosphodiesterase. 10 The family shares amino acid similarity with the PSO2/SNM1 family of DNA interstrand crosslink repair proteins. Furthermore, a potential ATP/GTP-binding motif suggests that ELAC2 may possess ATPase/GTPase activity. The function of this protein has yet to be elucidated, and the functional significance of the cancer-associated missense mutations is not known.In our study, we investigate the properties of the protein encoded by the candidate prostate cancer susceptibility gene, ELAC2, and demonstrate a physical interaction with components of the ␥-tubulin complex.

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Section: Discussionmentioning

confidence: 71%

The product of the candidate prostate cancer susceptibility gene ELAC2 interacts with the γ‐tubulin complex

Korver¹,

Guevara²,

Chen

et al. 2003

Intl Journal of Cancer

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“…Our results lead us to argue that allelic loss constitutes a category of genetic abnormalities implicated in tumor progression and may be caused in part by chromosomal instability putatively associated with short telomeres of tumor cell chromosomes. Nevertheless, loss of normal centrosome regulation and function,40 partial inactivation of DNA repair pathways41 and demethylation of chromosomal segments42 leading to chromosomal instability could also play a significant role in allelic losses during tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma

et al. 2001

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Colorectal carcinogenesis is widely accepted as one of the best-characterized examples of stepwise progression. The existing colorectal carcinogenesis model assumes genetic homogeneity of individual tumors for the main known genetic alterations: K-ras and p53 genes point mutations and loss of heterozygosity (LOH) of chromosome 5q and 18q. The object of the present study was to demonstrate the existence of an intratumor genetic heterogeneity in advanced sporadic colorectal carcinoma for these genetic alterations. Using improved tissue microdissection and DNA extraction, for each tumor, amplifiable DNA was obtained from 15 to 20 areas, of which 1 to 2 concerned lymph node metastases (LNM). This study revealed that 10 of 15 (67%) analyzed tumors were heterogeneous for at least 1 genetic alteration, with between 2 and 6 genotypically different clones detected per tumor. No correlation was observed between the genotype of these subclones and histological differentiation or invasive propensity. Intratumor heterogeneity was more frequently observed for LOH than for point mutations, 67% and 58% for LOH at APC and DCC locus, and 20% for mutation of either the K-ras or p53 gene. In 5 of the 9 (56%) heterogeneous cases with available LNM, the genotype observed in the LNM was different from that of the main clone in the primary tumor, and moreover, 2 of the LNM displayed a genotype undetected in the primary tumor. In conclusion, intratumor genetic heterogeneity was demonstrated in advanced sporadic colorectal carcinoma and was represented as topographically distinct genotypic subclones. Taking into account such a significant genetic heterogeneity of colorectal tumors, the use of genetic markers for prognosis management should be reconsidered.

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“…In addition to PKA, several kinases involved in regulation of cell cycle progression are localized at the centrosome and mitotic spindle poles. These include Cdk2, Cdk4/6, polo-like and aurora kinases, pEg2 and others (Balczon 1996, Whitehead & Salisbury 1999, Nigg 2001. Mutations of pololike kinase-1 result in centrosome abnormalities and chromosomal instability in rodent cells (Smith et al 1997, Zhou et al 1998.…”

Section: Prkar1a and Chromosome Stabilitymentioning

confidence: 99%

Protein kinase A and its role in human neoplasia: the Carney complex paradigm.

Bossis¹,

Voutetakis²,

Bei³

et al. 2004

Endocr Relat Cancer

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The type 1 alpha regulatory subunit (R1a) of cAMP-dependent protein kinase A (PKA) (PRKAR1A) is an important regulator of the serine-threonine kinase activity catalyzed by the PKA holoenzyme. Carney complex (CNC) describes the association 'of spotty skin pigmentation, myxomas, and endocrine overactivity'; CNC is in essence the latest form of multiple endocrine neoplasia to be described and affects the pituitary, thyroid, adrenal and gonadal glands. Primary pigmented nodular adrenocortical disease (PPNAD), a micronodular form of bilateral adrenal hyperplasia that causes a unique, inherited form of Cushing syndrome, is also the most common endocrine manifestation of CNC. CNC and PPNAD are genetically heterogeneous but one of the responsible genes is PRKAR1A, at least for those families that map to 17q22-24 (the chromosomal region that harbors PRKAR1A). CNC and/or PPNAD are the first human diseases to be caused by mutations in one of the subunits of the PKA holoenzyme. Despite the extensive literature on R1a and PKA, little is known about their potential involvement in cell cycle regulation, growth and/or proliferation. The presence of inactivating germline mutations and the loss of its wild-type allele in CNC lesions indicated that PRKAR1A could function as a tumor-suppressor gene in these tissues. However, there are conflicting data in the literature about PRKAR1A's role in human neoplasms, cancer cell lines and animal models. In this report, we review briefly the genetics of CNC and focus on the involvement of PRKAR1A in human tumorigenesis in an effort to reconcile the often diametrically opposite reports on R1a.

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Regulation and regulatory activities of centrosomes

Cited by 17 publications

References 34 publications

The product of the candidate prostate cancer susceptibility gene ELAC2 interacts with the γ‐tubulin complex

The product of the candidate prostate cancer susceptibility gene ELAC2 interacts with the γ‐tubulin complex

Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma

Protein kinase A and its role in human neoplasia: the Carney complex paradigm.

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