Melanomas, from the cell cycle point of view (Review).

Halaban, Ruth; Miglarese, Mark; Smicun, Yoel; Puig, Sònia

doi:10.3892/ijmm.1.2.419

Cited by 23 publications

(38 citation statements)

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“…It was further speculated that the reduction of pRb-activity due to hyperphosphorylation could be a causal principle of unlimited growth of melanoma. 3,4 To the best of our knowledge, this is the first report on p-pRb in in vivo samples of cutaneous malignant melanomas. Employing currently available phosphorylation site-directed antibodies, we have analyzed three out of 16 possible phosphorylation sites of pRb.…”

Section: Discussionmentioning

confidence: 88%

“…2 Also in malignant melanomas, the loss of cell cycle control is thought to be due to a lack of pRb activity and not to lack of expression or mutation. 3,4 Currently, the concept is arguably accepted that persistent inactivation and hyperphosphorylation of wild-type pRb in melanomas is caused by a sustained cyclindependent kinase (cdk) activity. [5][6][7] In uveal malignant melanomas, Brantley et al 8,9 have recently reported an increased pRb phosphorylation at Ser807/811.…”

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confidence: 99%

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Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma

et al. 2005

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Mutation, absence or abnormal functioning of retinoblastoma protein are fundamental elements of uncontrolled growth in human cancer. In this study, we analyze the expression of retinoblastoma protein and phosphorylated retinoblastoma protein in melanocytic tumors in vivo. Real-time RT-PCR and immunohistochemistry (tissue microarrays and conventional histological sections) reveal that retinoblastoma protein is progressively upregulated in advanced and metastatic malignant melanomas in vivo. However, this increase is paralleled by increased retinoblastoma protein inactivation due to protein phosphorylation. Interestingly, retinoblastoma protein phosphorylation occurs not homogeneously, but with a 'growth zone'-related pattern. In superficial spreading melanomas a subepidermal-lateral maximum of phosphorylated retinoblastoma protein can be frequently observed. Accordingly, nodular vertically invasive melanomas are characterized by a strong staining of phosphorylated retinoblastoma protein in deep-dermal invading protrusions of the tumor. Furthermore, Kaplan-Meier analysis of 13 cases of advanced melanomas with long-time follow-up suggests a significant negative impact of retinoblastoma protein phosphorylation on survival of melanoma patients independent of tumor thickness. We conclude that the evaluation of phosphorylated retinoblastoma protein in melanocytic tumors could become a helpful adjunct in clinicopathological routine. The main principle of cell cycle homeostasis is the phosphorylation-dependent activation and deactivation of regulatory proteins upstream of retinoblastoma protein (pRb), which represents the central cycle-controlling element. At the G1/S transition, the antiproliferative function of active, hypophosphorylated pRb is mediated by its binding capacity to proproliferative transcription factors such as E2F, c-Myc, ATF-2 and c-Abl. 1 Surprisingly, with the exception of retinoblastoma, osteosarcoma and small cell lung carcinoma, the overall rate of pRbmutations in the vast majority of human cancers is either extremely low or not existent. 2 Also in malignant melanomas, the loss of cell cycle control is thought to be due to a lack of pRb activity and not to lack of expression or mutation. 3,4 Currently, the concept is arguably accepted that persistent inactivation and hyperphosphorylation of wild-type pRb in melanomas is caused by a sustained cyclindependent kinase (cdk) activity. [5][6][7] In uveal malignant melanomas, Brantley et al 8,9 have recently reported an increased pRb phosphorylation at Ser807/811. Since they have also detected a high cyclin D expression, the hypothesis of a functional inactivation of pRb due to cyclin-and cdk-dependent hyperphosphorylation was further substantiated.To the best of our knowledge, no detailed studies have been performed to elucidate the pRb phosphorylation status in in vivo samples of cutaneous melanocytic tumors. In particular, studies on the impact of hyperphosphorylated pRb on melanoma progression are still lacking. Therefore, in this study we analyze to...

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Section: Discussionmentioning

confidence: 88%

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confidence: 99%

Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma

et al. 2005

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“…In addition, more problematic scenarios arise from the well-established non-catalytic functions of cyclin D1 and its ability to titrate the CDK2 inhibitors p27 Kip1 and p21 Cip1 . Sequestration or loss of those CKIs has been previously shown to promote aberrant Rb phosphorylation and cell-cycle progression (Halaban et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

et al. 2010

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A hallmark of cancer is the deregulation of cell-cycle machinery, ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, cyclin D1 has a crucial role in the development of disease. Recently, a highly specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast cancer. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated on a panel of breast cancer cell lines. These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies showed a highly specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F, and the ability to attenuate CDK2 activity. Acquired resistance to PD-03322991 was specifically associated with attenuation of CDK2 inhibitors, indicating that redundancy in CDK functions represents a determinant of therapeutic failure. Despite these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.

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“…Thus, we suggest that, at least in case of these 23 genes, RBP2-H1 might exert transcriptional control by direct interaction with respective regulatory chromosomal elements. Within this intersectional group of genes, the melanoma-relevant genes JAG-1 [48][49][50] and CDK6 [35][36][37][38] were included as well as 1 new candidate melanoma gene, DYRK1A, which was reported to be downregulated in highly metastatic melanoma cells. [63][64][65] RBP2-H1/JARID1B re-expression re-constitutes anti-tumorigenic mechanisms in melanoma cells…”

Section: Rbp2-h1/jarid1b Binds To a Multitude Of Human Chromosomal Rementioning

confidence: 99%

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

Roesch

Mueller²,

Stempfl

et al. 2007

Intl Journal of Cancer

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The RBP2-H1/JARID1B nuclear protein belongs to the ARID family of DNA-binding proteins and is a potential tumor suppressor that is lost during melanoma development. As we have recently shown, one physiological function of RBP2-H1/JARID1B is to exert cell cycle control via maintenance of active retinoblastoma protein. We now add new evidence that RBP2-H1/JARID1B can also directly regulate gene transcription in a reporter assay system, either alone or as part of a multimolecular complex together with the developmental transcription factors FOXG1b and PAX9. In melanoma cells, chromatin immunoprecipitation combined with promoter chip analysis (ChIP-on-chip) suggests a direct binding of re-expressed RBP2-H1/JARID1B to a multitude of human regulatory chromosomal elements (promoters, enhancers and introns). Among those, a set of 23 genes, including the melanoma relevant genes CDK6 and JAG-1 could be confirmed by cDNA microarray analyses to be differentially expressed after RBP2-H1/JARID1B re-expression. In contrast, in nonmelanoma HEK 293 cells, RBP2-H1/JARID1B overexpression only evokes a minor transcriptional response in cDNA microarray analyses. Because the transcriptional regulation in melanoma cells is accompanied by an inhibition of proliferation, an increase in caspase activity and a partial cell cycle arrest in G1/0, our data support an anti-tumorigenic role of RBP2-H1/JARID1B in melanocytic cells. ' 2007 Wiley-Liss, Inc.Key words: melanoma; transcription; gene expression; retinoblastoma protein binding protein; apoptosisIn 1999, our group detected a gene transcript suppressed by UV-B in normal human melanocytes (Acc. No. AF087481, 1 ). Based on its homology to the previously described RBP2, 2 this new gene was termed retinoblastoma binding protein 2-homolog 1 (RBP2-H1). Subsequent expression studies revealed a frequent loss of RBP2-H1 in the majority of advanced and metastatic melanomas in vivo and in many melanoma cell lines, whereas benign melanocytic tumors, normal tissues and other cancer types mostly retain RBP2-H1. 1,3 Recently, we showed that RBP2-H1 has a tumor suppressive activity partly due to binding and stabilization of hypophosphorylated retinoblastoma protein (pRb) leading to maintenance of pRb-mediated cell cycle control. 4 As a result of truncation studies, we located the pRb-binding activity of RBP2-H1 to its C-term, containing a homolog region of the non-T/E1A-pRb binding domain known from other retinoblastoma binding proteins like RBP2. 5 Moreover, RBP2-H1 and its splicing variants PLU-1 and RBBP2H1a contain further well-conserved domains known to be involved in direct gene regulation and chromatin homeostasis, e.g. 3 PHD motifs and the ARID (AT-rich interacting) DNA-binding domain. [6][7][8][9] Although the 3 splicing variants show a cDNA sequence homology of more than 98%, RBP2-H1 differs from PLU-1 and RBBP2H1a by an additional exon encoding a region with strong homology to chromosomal ALU repeats. Thus, previously reported differences in tissue expression (PLU-1 shows a restricted expre...

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Melanomas, from the cell cycle point of view (Review).

Cited by 23 publications

References 0 publications

Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma

Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma

Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure

RBP2‐H1/JARID1B is a transcriptional regulator with a tumor suppressive potential in melanoma cells

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