Cyclin D2 and cyclin D3 play opposite roles in mouse skin carcinogenesis

Rojas, Paulina S.; Cadenas, María Belén; Lin, Pei; Benavides, Fernando; Conti, Claudio J.; Rodriguez‐Puebla, Marcelo L.

doi:10.1038/sj.onc.1209970

Cited by 20 publications

(35 citation statements)

References 28 publications

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“…These results highlighted the oncogenic properties of D-type cyclins, CDK4 and CDK6. Surprisingly, however, carcinogen-induced skin tumorigenesis was compromised by transgenic overexpression of cyclin D3 or CDK6 in mice 14, 15 , whereas cyclin D1, D2 or CDK4 overexpression enhanced skin tumorigenesis as expected 14, 16, 17 .…”

Section: Cell Cycle Proteins and Their Role In Physiology And Cancermentioning

confidence: 75%

“… CCND1 gain:Hepatocellular carcinomas 251 Skin papillomas (DMBA) 16 B-cell lymphomas 252 Mammary cancer 13 CCND2 gain:Skin carcinomas (DMBA+TPA) 14 CCND3 gain:Skin carcinomas (DMBA+TPA) 14 Mammary cancer 253 CDK4 gain:Skin tumours (DMBA+TPA) 12, 17 Pituitary, pancreatic tumours ( Men1 +/− ) 54 Pituitary carcinomas ( Cdkn1b −/− ) 254 Endocrine tumours, haemangiomas 11 CDK6 gain:Skin papillomas (DMBA+TPA) 15 CCNE1 gain:Mammary cancer ( Trp53 +/− ) 255 Mammary cancer 45 Lung cancer 256 Lung cancer ( Kras G12D/+ ) 257 Pituitary adenomas 258 T-cell lymphomas ( Cdkn1b −/− ) 259 CCNB1/2 gain:Lung cancer 64 Skin tumours (DMBA) 64 Intestinal adenocarcinomas ( Apc Min/+ ) 64 AURKA gain:Skin carcinomas (DMBA+TPA) 260 Mammary cancer 107 AURKB gain:Lymphomas 102 Ccnd1 loss:Intestinal adenomas ( Apc Min/+ ) 261 Skin carcinomas ( v-Hras +TPA, DMBA+TPA) 262 Rhabdoid tumours ( Ini1 +/− ) 263 Mammary cancer ( Erbb2 V664D , v-Hras ) 18, 19 Mammary cancer ( Erbb2 V664D ) 22, 26 Ccnd2 loss:Intestinal adenomas ( Apc Min/+ ) 264 Ovarian, testicular, adrenal tumours ( Inha −/− ) 265 Skin carcinomas (DMBA+TPA) 14 Ccnd3 loss:

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Section: Figurementioning

confidence: 99%

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Cell cycle proteins as promising targets in cancer therapy

2017

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Preface Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins; therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrated that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. In contrast, many cancers are uniquely dependent on these proteins and are hence selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. Here, we review the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as future therapeutic potential of various inhibitors. We focus only on proteins that directly regulate cell cycle progression. Cyclin-dependent kinases with transcriptional functions, as well as PARP inhibitors, which are highly successful in targeting BRCA1/BRCA2-mutant tumours, are not covered by this review.

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Section: Cell Cycle Proteins and Their Role In Physiology And Cancermentioning

confidence: 75%

…”

Section: Figurementioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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“…Whether CCND2/Cdk6 is more efficient in the phosphorylation of Rb than CCND1/Cdk4 during liver tumor development warrants further investigation, and may provide functional roles for CCND2 in hepatic carcinogenesis. A recent study supports a positive role for cyclin D2 in tumorigenesis, where cyclin D2 transgenic mice are more susceptible to developing skin tumors, a characteristic that is not shared by cyclin D1 and D3 transgenic mice generated under the same promoter (46, 47). In addition, D-type cyclins play Cdk-independent roles in certain cell types.…”

Section: Discussionmentioning

confidence: 90%

Role of Cyclin D1 as a Mediator of c-Met– and β-Catenin–Induced Hepatocarcinogenesis

Patil¹,

Lee²,

Macías

et al. 2008

Cancer Research

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Activation of c-Met signaling and B-catenin mutations are frequent genetic events observed in liver cancer development. Recently, we demonstrated that activated B-catenin can cooperate with c-Met to induce liver cancer formation in a mouse model. Cyclin D1 (CCND1) is an important cell cycle regulator that is considered to be a downstream target of B-catenin. To determine the importance of CCND1 as a mediator of c-Met-and B-catenin-induced hepatocarcinogenesis, we investigated the genetic interactions between CCND1, B-catenin, and c-Met in liver cancer development using mouse models. We coexpressed CCND1 with c-Met in mice and found CCND1 to cooperate with c-Met to promote liver cancer formation. Tumors induced by CCND1/c-Met had a longer latency period, formed at a lower frequency, and seemed to be more benign compared with those induced by B-catenin/c-Met. In addition, when activated B-catenin and c-Met were coinjected into CCND1-null mice, liver tumors developed despite the absence of CCND1. Intriguingly, we observed a moderate accelerated tumor growth and increased tumor malignancy in these CCND1-null mice. Molecular analysis showed an up-regulation of cyclin D2 (CCND2) expression in CCND1-null tumor samples, indicating that CCND2 may replace CCND1 in hepatic tumorigenesis. Together, our results suggest that CCND1 functions as a mediator of B-catenin during HCC pathogenesis, although other molecules may be required to fully propagate B-catenin signaling. Moreover, our data suggest that CCND1 expression is not essential for liver tumor development induced by c-Met and Bcatenin. [Cancer Res 2009;69(1):253-61]

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“…Of note, although Cyclin D1 and Cyclin D2 are widely known for their role in G1-phase progression, Cyclin D3 function is still unclear. Indeed, a transcriptional regulatory activity of this Cyclin has been reported in several tissues, where it appears to promote cell cycle exit, thereby favoring differentiation [47][48][49] . To our knowledge, the role of Cyclin D3 in reactive Müller cells remains unknown and its link with YAP in Müller glia cell cycle reentry thus remains to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

Linking YAP to Müller glia quiescence exit in the degenerative retina

Hamon

Ail

García-García

et al. 2018

Preprint

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Contrasting with fish or amphibian, retinal regeneration from Müller glial cells is largely limited in mammals. In our quest towards the identification of molecular cues that may boost their stemness potential, we investigated the involvement of the Hippo pathway effector YAP, which we previously found to be upregulated in Müller cells following retinal injury. We report that conditional Yap deletion in Müller cells prevents the upregulation of cell cycle genes that normally accompanies reactive gliosis upon photoreceptor cell death. This occurs as a consequence of defective EGFR signaling. Consistent with a function of YAP in triggering Müller glia cell cycle re-entry, we further show that in Xenopus, a species endowed with efficient regenerative capacity, YAP is required for their injurydependent proliferative response. Finally, and noteworthy, we reveal that YAP overactivation in mouse Müller cells is sufficient to induce their reprogramming into highly proliferative cells. Overall, we unravel a pivotal role for YAP in tuning Müller cell response to injury and highlight a novel YAP-EGFR axis by which Müller cells exit their quiescence state, a critical step towards regeneration. Key words: Müller cells, reactive gliosis, retinal regeneration, Hippo/YAP pathway, EGFRpathway Neurodegenerative retinal diseases, such as retinitis pigmentosa or age-related macular degeneration, ultimately lead to vision loss, as a consequence of photoreceptor cell death. Driving retinal self-repair from endogenous neural stem cells in patients represents an attractive therapeutic strategy. Among cellular sources of interest are Müller cells, the major glial cell type in the retina. These cells are essential for maintaining retinal homeostasis 1 but also proved their potential for endogenous regeneration. In certain species, such as zebrafish or Xenopus, they behave as genuine stem cells, endowed with the ability to reprogram into a progenitor-like state upon retinal damage, proliferate and regenerate lost photoreceptors 2-4 . In mammals, however, their proliferative response to injury is extremely limited. Following acute retinal damage, mouse Müller glial cells rapidly re-enter G1-phase of the cell cycle, as inferred by increased cyclin gene expression, but they rarely divide 5 . Suggesting that they nonetheless retain remnants of repair capacities, their proliferation and neurogenic potential can be stimulated, for instance by supplying exogenous growth factors such as Heparin-binding EGF-like growth factor (HB-EGF), or by overexpressing the proneural gene Ascl1a 3,6-8 . Our understanding of the genetic/signaling network sustaining Müller cell stemness potential is however far from being complete. Identifying novel molecular cues is thus of utmost importance to foresee putative candidates that could be targeted for regenerative medicine. We here investigated whether the Hippo pathway effector YAP might influence Müller cell reactivation and how it would intersect with other critical signaling pathways. The Hippo pathway is a kina...

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Cyclin D2 and cyclin D3 play opposite roles in mouse skin carcinogenesis

Cited by 20 publications

References 28 publications

Cell cycle proteins as promising targets in cancer therapy

Cell cycle proteins as promising targets in cancer therapy

Role of Cyclin D1 as a Mediator of c-Met– and β-Catenin–Induced Hepatocarcinogenesis

Linking YAP to Müller glia quiescence exit in the degenerative retina

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