Modulation of Cell Cycle Components by Epigenetic and Genetic Events

Macaluso, Marcella; Montanari, Micaela; Cinti, Caterina; Giordano, Antonio

doi:10.1053/j.seminoncol.2005.07.009

Cited by 74 publications

(49 citation statements)

References 79 publications

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“…The retinoblastoma (RB) regulatory pathway of cell cycle control is deregulated in virtually all human tumour types (Cobrinik, 2005;Korenjak and Brehm, 2005;Macaluso et al, 2005). In a physiological cell state, the ability of the retinoblastoma protein (pRb) to control cell cycle progression via binding members of the E2F transcription factor family is controlled by cyclin D/cdk4-mediated phosporylation.…”

mentioning

confidence: 99%

Independent prognostic significance of cell cycle regulator proteins p16INK4a and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group

et al. 2007

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The purpose of the study is to test the hypothesis that expression of cell cycle regulatory proteins p16 INK4a and pRb is significantly associated with prognosis in ovarian carcinomas. We performed immunohistochemical analysis of p16 INK4a and pRb expression and correlated with survival in a series of 300 patients with FIGO stage IIb-IV ovarian carcinoma which were enrolled in a randomized prospective trial evaluating two different platinum and paxlitaxel chemotherapy combinations after radical surgery. p16 INK4a negative tumours (17/300; 6%) had a significantly worse prognosis (univariate analysis, Po0.001; multivariate analysis: odds ratio 2.41, P ¼ 0.009). Among p16 INK4a -positive tumours (283 out of 300; 94%), survival was better for patients with intermediate expression as compared to low or high expression levels (P ¼ 0.001). High expression levels of pRb were associated with an incremental deterioration of prognosis (univariate analysis, P ¼ 0.004; multivariate analysis: odds ratio 2.98, P ¼ 0.002). This observation held also true in the subgroup of optimally debulked patients (n ¼ 82), in whom the most important established prognostic factor, postoperative residual tumour cannot be applied. In conclusion p16 INK4a and pRb are independent prognostic factors in advancedstage ovarian carcinomas after radical surgery and postoperative chemotherapy. High pRb expression is a significant prognosticator in optimally debulked patients and may hold potential for subgroup stratification in postoperative treatment.

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confidence: 99%

Independent prognostic significance of cell cycle regulator proteins p16INK4a and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group

et al. 2007

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“…How pRb family members control cell cycle proliferation is not completely understood. Moreover, the interaction between the pRb family proteins and the E2F family transcription factors plays a central role in governing cell cycle progression and DNA replication by controlling the expression of cell cycle E2F-dependent genes (Macaluso et al, 2005). In addition, pRb recruits chromatin remodeling factors such as histone deacetylase 1 (HDAC1) (Luo et al, 1998), SWI/SNF factors (Harbour and Dean, 2000;De Luca et al, 1997), Polycomb group proteins (Dahiya et al, 2001) or methyltransferase (Nielsen et al, 2001) that act on the nearby surrounding nucleosome structure.…”

Section: Introductionmentioning

confidence: 99%

RB and cell cycle progression

2006

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The Rb protein is a tumor suppressor, which plays a pivotal role in the negative control of the cell cycle and in tumor progression. It has been shown that Rb protein (pRb) is responsible for a major G1 checkpoint, blocking S-phase entry and cell growth. The retinoblastoma family includes three members, Rb/p105, p107 and Rb2/p130, collectively referred to as 'pocket proteins'. The pRb protein represses gene transcription, required for transition from G1 to S phase, by directly binding to the transactivation domain of E2F and by binding to the promoter of these genes as a complex with E2F. pRb represses transcription also by remodeling chromatin structure through interaction with proteins such as hBRM, BRG1, HDAC1 and SUV39H1, which are involved in nucleosome remodeling, histone acetylation/ deacetylation and methylation, respectively. Loss of pRb functions may induce cell cycle deregulation and so lead to a malignant phenotype. Gene inactivation of pRB through chromosomal mutations is one of the principal reasons for retinoblastoma tumor development. Functional inactivation of pRb by viral oncoprotein binding is also shown in many neoplasias such as cervical cancer, mesothelioma and AIDS-related Burkitt's lymphoma.

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“…In addition to loss of nuclear p27 expression, cytoplasmic mislocalization of p27 has been observed in colon cancer [7]. In various cancers, cytoplasmic p27 mislocalization has been associated with activated AKT1 (protein kinase B) [8,9], overexpression of cyclin D3 [10], and poor prognosis [1,11]. However, biological implications and differences between p27 loss and p27 mislocalization in colorectal cancer, particularly in relation to other molecular alterations, have not been comprehensively evaluated.…”

Section: Introductionmentioning

confidence: 99%

“…Progression through the cell cycle involves sequential activation and inactivation of cyclindependent kinases (CDKs) [1]. CDKs are activated through association with positive regulators (cyclins) and inactivated by cyclin-CDK inhibitors.…”

Section: Introductionmentioning

confidence: 99%

“…CDKs are activated through association with positive regulators (cyclins) and inactivated by cyclin-CDK inhibitors. p27 {CDKN1B (cyclin-dependent kinase inhibitor 1B) / KIP1} is one of the cyclin-CDK inhibitors and plays a key role in preventing progression into S phase of the cell cycle [1]. Regulation of p27 levels is achieved posttranslationally through ubiquitin-mediated protein degradation [2].…”

Section: Introductionmentioning

confidence: 99%

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Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator phenotype

Ogino¹,

Kawasaki²,

Ogawa³

et al. 2007

Human Pathology

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Cytoplasmic mislocalization of p27 (cyclin-dependent kinase inhibitor-1B, CDKN1B/KIP1) is caused by activated AKT1, and has been associated with poor prognosis in various cancers. CpG island methylator phenotype (CIMP) in colorectal cancer is characterized by extensive promoter methylation, and is associated with microsatellite instability-high (MSI-H) and BRAF mutations. We have recently shown a positive correlation between MSI/CIMP and loss of nuclear p27. However, no study has examined cytoplasmic p27 mislocalization in relation to CIMP and MSI in colorectal cancer. Using MethyLight assays, we quantified DNA methylation in eight CIMP-specific gene promoters {CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1} in 853 colorectal cancer samples obtained from two large prospective cohorts. We assessed expressions of nuclear and cytoplasmic p27 and nuclear p53 by immunohistochemistry. Cytoplasmic p27 expression was inversely associated with loss of nuclear p27 (p<0.0001), CIMP-high (p<0.0001), MSI-H (p<0.0001) and BRAF mutations (p<0.0001). The inverse association of cytoplasmic p27 with CIMP-high (or MSI-H) was independent of MSI (or CIMP) status. In addition, the inverse association of cytoplasmic p27 with CIMP-high was independent of KRAS/BRAF status. BRAF and CDKN2A (p16) methylation were not correlated with cytoplasmic p27 after stratification by CIMP status. The inverse associations of cytoplasmic p27 with MSI-H and CIMP-high were much more pronounced in p53-negative tumors than p53-positive tumors. In conclusion, cytoplasmic p27 expression is inversely associated with MSI-H and CIMP-high, particularly in p53-negative tumors, suggesting interplay of functional losses of p27 and p53 in the development of various molecular subtypes of colorectal cancer.

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Modulation of Cell Cycle Components by Epigenetic and Genetic Events

Cited by 74 publications

References 79 publications

Independent prognostic significance of cell cycle regulator proteins p16INK4a and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group

Independent prognostic significance of cell cycle regulator proteins p16INK4a and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group

RB and cell cycle progression

Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator phenotype

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