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

Platz, Anton; Sevigny, P; Norberg, Torbjörn; P, Ring; Lagerlöf, B.; Ringborg, Ulrik

doi:10.1038/bjc.1996.460

Cited by 20 publications

(10 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The tumorigenic role of sunlight in SCC may be related to UV-associated mutations in p53 which are C=T and CC=TT transitions (Brash et al, 1991). UV-associated mutations have also been detected in cell cycle regulating genes in malignant melanoma (Platz et al, 1996). Our results support the notion that patients with SCC should avoid excessive sun exposure because of the high risk of developing second primary malignancies of the skin.…”

Section: Discussionsupporting

confidence: 79%

Second primary cancers in patients with squamous cell carcinoma of the skin: A population-based study in Sweden

et al. 1999

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 79%

Second primary cancers in patients with squamous cell carcinoma of the skin: A population-based study in Sweden

et al. 1999

View full text Add to dashboard Cite

“…25 The CDKN2B gene, in addition to being co-deleted along with the CDKN2A gene in a number of cancers, is occasionally targeted independently in tumours including melanoma. 11,26 The dynamics of expression favour the role of CDKN2A over the other members of the CDK4/6 inhibitor family, as a guardian against cell proliferation; loss of function in many tumours is consistent with this role. 27 The inactivation of the CDKN2C gene in human tumours is rare, albeit not completely absent.…”

Section: Discussionmentioning

confidence: 97%

“…11 The two additional members of the CDKN2 family of genes CDKN2C and CDKN2D, which encode CDK4/6 inhibitors p18 INK4c and p19 INK4c , respectively, have also been considered as possible targets of inactivation in a few cancer types. 12,13 The other potential targets of inactivation considered, based on melanoma cell line studies, are the genes encoding the components of the retinoblastoma cell cycle pathway.…”

mentioning

confidence: 99%

A single nucleotide polymorphism in the 3?untranslated region of theCDKN2A gene is common in sporadic primary melanomas but mutations in theCDKN2B,CDKN2C,CDK4 andp53 genes are rare

Kumar¹,

Smeds²,

Berggren³

et al. 2001

Int. J. Cancer

View full text Add to dashboard Cite

Ten patients with advanced B-cell lymphoma were treated with a single locoregional injection of CD3CD19 bispecific and costimulating CD28 monospecific antibodies to activate tumor-infiltrating T-lymphocytes. Antibodies were administered at 4 different dose levels (30 g, 270 g, 810 g, 1,600 g of each antibody) either by intratumoral or intralym-phatic injection. Most patients developed responses within different compartments of the immune systems (T cells, NK cells) subsequent to the antibody application. Comparative studies in 2 patients of which treated as well as untreated lymph nodes were available revealed the up-regulation of T-cell activation markers induced by the antibody injection. Additionally, in 1 patient the induction of apoptosis of lym-phoma B cells in the antibody-treated lymph node was observed. Specificity analyses of peripheral blood T cells by means of IFN-ELISpot measurement indicated the recruitment of idiotype-specific T cells, as in 1 out of 3 investigated patients an increased T-cell response toward autologous id-iotype peptides could be demonstrated. We conclude that a single injection of CD3CD19 bispecific antibodies is capable to induce an activation of autologous T lymphocytes if simultaneous costimulatory signaling by CD28 antibodies is provided. Furthermore, our data suggest that at least in some patients lymphoma-specific T cells can be recruited by this immunotherapeutic approach toward B-cell lymphoma. Among the immunotherapeutic approaches toward malignant diseases of B-cell origin, strategies aiming at the activation of T lymphocytes are most promising as these are known to be highly specialized effector cells of the cellular immune system mediating key functions such as cytotoxicity, cytokine production, regulation of other effector cells, and immunological memory. The central role of T lymphocytes in the regulation of the immune system is the rationale for the therapeutic use of professional antigen-presenting cells (APC), namely dendritic cells (DC), that can process and present tumor-associated antigens (TAA) and thus are able to activate tumor-specific T lymphocytes. 1 APC-based approaches for the induction of anti-tumoral T-cell responses are therefore being tested in clinical studies in several human malignancies including B-cell lymphomas and myeloma. 2,3 Tumor-specific T-cell activation by non-cellular immunothera-peutic agents avoids the requirement to generate autologous DC ex vivo for every individual patient. In this view, CD3-based bispe-cific antibodies (CD3anti-TAA) may be used alternatively or in addition to vaccination protocols with DC as they can stimulate T cells in a tumor-specific manner as well. 4 As the application of CD3anti-TAA bispecific antibodies alone will result in an insufficient activation or even apoptosis of the effector cells, 5 the additional stimulation of the effector T cells is an indispensable demand. To address this problem, we used locoregional (i.e., intratumoral) injections of CD3CD19 bispecific antibodies targeting the B-cell anti...

show abstract

“…The vast majority of mutations that contribute to cancer cell proliferation and survival are in genes that regulate progression through G1 phase of the cell cycle [1,2]. A key regulatory site in G1 is the growth factor (GF)-dependent restriction point (R), originally described by Pardee [3], where cells receive permissive signals to progress through G1 and divide.…”

Section: Introductionmentioning

confidence: 99%

Amino Acids and mTOR Mediate Distinct Metabolic Checkpoints in Mammalian G1 Cell Cycle

et al. 2013

View full text Add to dashboard Cite

ObjectiveIn multicellular organisms, cell division is regulated by growth factors (GFs). In the absence of GFs, cells exit the cell cycle at a site in G1 referred to as the restriction point (R) and enter a state of quiescence known as G0. Additionally, nutrient availability impacts on G1 cell cycle progression. While there is a vast literature on G1 cell cycle progression, confusion remains – especially with regard to the temporal location of R relative to nutrient-mediated checkpoints. In this report, we have investigated the relationship between R and a series of metabolic cell cycle checkpoints that regulate passage into S-phase.MethodsWe used double-block experiments to order G1 checkpoints that monitor the presence of GFs, essential amino acids (EEAs), the conditionally essential amino acid glutamine, and inhibition of mTOR. Cell cycle progression was monitored by uptake of [3H]-thymidine and flow cytometry, and analysis of cell cycle regulatory proteins was by Western-blot.ResultsWe report here that the GF-mediated R can be temporally distinguished from a series of late G1 metabolic checkpoints mediated by EAAs, glutamine, and mTOR – the mammalian/mechanistic target of rapamycin. R is clearly upstream from an EAA checkpoint, which is upstream from a glutamine checkpoint. mTOR is downstream from both the amino acid checkpoints, close to S-phase. Significantly, in addition to GF autonomy, we find human cancer cells also have dysregulated metabolic checkpoints.ConclusionThe data provided here are consistent with a GF-dependent mid-G1 R where cells determine whether it is appropriate to divide, followed by a series of late-G1 metabolic checkpoints mediated by amino acids and mTOR where cells determine whether they have sufficient nutrients to accomplish the task. Since mTOR inhibition arrests cells the latest in G1, it is likely the final arbiter for nutrient sufficiency prior to committing to replicating the genome.

show abstract

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

Cited by 20 publications

References 29 publications

Second primary cancers in patients with squamous cell carcinoma of the skin: A population-based study in Sweden

Second primary cancers in patients with squamous cell carcinoma of the skin: A population-based study in Sweden

A single nucleotide polymorphism in the 3?untranslated region of theCDKN2A gene is common in sporadic primary melanomas but mutations in theCDKN2B,CDKN2C,CDK4 andp53 genes are rare

Amino Acids and mTOR Mediate Distinct Metabolic Checkpoints in Mammalian G1 Cell Cycle

Contact Info

Product

Resources

About