Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic <i>ras</i> pathway in vivo

Robles, Ana I.; Rodriguez‐Puebla, Marcelo L.; Glick, Adam B.; Trempus, Carol S.; Hansen, Laura A.; Siciński, Piotr; Tennant, Raymond W.; Weinberg, Robert A.; Yuspa, Stuart H.; Conti, Claudio J.

doi:10.1101/gad.12.16.2469

Cited by 217 publications

(201 citation statements)

References 29 publications

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“…To begin to define the role of Ral activation in growth control, we examined the consequences of Ral expression on gene regulatory responses that are downstream of Ras activation and required for oncogenic Ras-induced transformation. The activation of SRE-dependent gene expression, induction of cyclin D1 protein expression, and activation of NF-B transcription factors have all been defined as critical events mediating Ras transformation (15,29,49) and are convergence points for multiple Ras-dependent signals (18,41,43,64).…”

Section: Resultsmentioning

confidence: 99%

Ral GTPases Contribute to Regulation of Cyclin D1 through Activation of NF-κB

Henry

Moskalenko

Kaur

et al. 2000

Molecular and Cellular Biology

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Section: Resultsmentioning

confidence: 99%

Ral GTPases Contribute to Regulation of Cyclin D1 through Activation of NF-κB

Henry

Moskalenko

Kaur

et al. 2000

Molecular and Cellular Biology

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“…We find it noteworthy that overexpression of cyclin D1 and cyclin D2, but not cyclin D3, was detected in premalignant lesions after 7,12-dimethylbenz[a]antracene (DMBA)/TPA applications (two-stage carcinogenesis protocol). 27 In this sense, cyclin D1 expression is necessary but not sufficient for development of skin tumors 41,42 because D1 knockout mice have a reduced number of papillomas whereas K5D1 mice did not have an increased number of skin tumors. We also performed carcinogenesis experiments using the two-stage protocol to test whether overexpression of cyclin D2 or cyclin D3 increased the susceptibility to chemical carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Cyclin D2 Overexpression in Transgenic Mice Induces Thymic and Epidermal Hyperplasia whereas Cyclin D3 Expression Results Only in Epidermal Hyperplasia

Rodriguez‐Puebla

LaCava

Marval

et al. 2000

The American Journal of Pathology

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In a previous report, we described the effects of cyclin D1 expression in epithelial tissues of transgenic mice. To study the involvement of D-type cyclins (D1, D2, and D3) in epithelial growth and differentiation and their putative role as oncogenes in skin, transgenic mice were developed which carry cyclin D2 or D3 genes driven by a keratin 5 promoter. As expected, both transgenic lines showed expression of these proteins in most of the squamous tissues analyzed. Epidermal proliferation increased in transgenic animals and basal cell hyperplasia was observed. All of the animals also had a minor thickening of the epidermis. The pattern of expression of keratin 1 and keratin 5 indicated that epidermal differentiation was not affected. Transgenic K5D2 mice developed mild thymic hyperplasia that reversed at 4 months of age. On the other hand, high expression of cyclin D3 in the thymus did not produce hyperplasia. The cyclins are a family of key cell-cycle regulators that function by association with and activation of cyclin-dependent kinases (CDKs) at specific points of the cell cycle to phosphorylate various proteins that are important during cell-cycle progression. 1 Three D-type cyclins (D1, D2, and D3) are expressed in the G 1 phase of the cell cycle and depending on cell lineage, various combinations of D-type cyclins are induced by mitogens. 1,2 Dtype cyclins form complexes with and activate CDK4 and CDK6 during the G 1 phase of the cell cycle. 3 A key substrate for G 1 cyclin/CDK complexes is the retinoblastoma protein, pRb. Phosphorylation of pRb, a tumor suppressor gene product, has been attributed to cyclin/CDK complexes and implicated in the regulation of proliferation in keratinocytes and other cell types. 4,5 Thus, phosphorylation of pRb blocks its ability to suppress the activity of S phase promoting transcription factors such as E2F. 4,6 Reconstitution of D-type cyclin/kinase complexes in baculovirus showed that all possible complexes are capable of phosphorylating pRb in vitro. 7,8 These results suggest that the fundamental role of D-type cyclins is to integrate extracellular signals with the cell-cycle machinery. 2 Initially, several reports assigned redundant roles to the three members of D-type cyclins, but in the last few years, it has become evident that each member plays a specific role and is differentially expressed in various tissues. 2 Recently, CDK-independent functions of D-type cyclins were also described. For example, ligand independent activation of estrogen receptors by cyclin D1 and inhibition of androgen receptors by binding of cyclin D1 or cyclin D3 was reported. 9 -12 Cyclin D1 and cyclin D2 seem to contribute to the neoplastic phenotypes in human and mouse tumors. In-

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“…Whereas a positive role of cyclin D1 was clearly established in mouse skin tumors (Robles et al, 1998), the question remained whether cyclin D2 is a mediator of keratinocyte transformation by oncogenic ras or is induced as a nonessential consequence of the proliferative response generated by ras transformation. To address these possibilities, we studied skin tumor development in cyclin D2-null mice.…”

Section: Molecular Analysis Of Keratinocytes Overexpressing Cyclin D3mentioning

confidence: 99%

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

Rojas¹,

Cadenas

Lin

et al. 2006

Oncogene

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D-type cyclins are components of the cell-cycle engine that link cell signaling pathways and passage throughout G1 phase. We previously described the effects of overexpression cyclin D1, D2 or D3 in mouse epidermis and tumor development. We now asked whether cyclin D2 and/or cyclin D3 play a relevant role in ras-dependent tumorigenesis. Here, we described the effect of cyclin D3 and cyclin D2 overexpression in mouse skin tumor development. Notably, overexpression of cyclin D3 results in reduced tumor development and malignant progression to squamous cell carcinomas (SCC). Biochemical analysis of keratinocytes shows that overexpression of cyclin D3 results in strong reduction of cyclin D2 and its associated kinase activity. Furthermore, we found that reinstatement of cyclin D2 level in the cyclin D3/cyclin D2 bigenic mice results in a complete reversion of the inhibitory action of cyclin D3. Supporting these results, ablation of cyclin D2 results in reduced tumorigenesis and malignant progression. On the other hand, overexpression of cyclin D2 results in an increased number of papillomas and malignant progression. We conclude that cyclin D3 and cyclin D2 play opposite roles in mouse skin tumor development and that the suppressive activity of cyclin D3 is associated with cyclin D2 downregulation.

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Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic ras pathway in vivo

Cited by 217 publications

References 29 publications

Ral GTPases Contribute to Regulation of Cyclin D1 through Activation of NF-κB

Ral GTPases Contribute to Regulation of Cyclin D1 through Activation of NF-κB

Cyclin D2 Overexpression in Transgenic Mice Induces Thymic and Epidermal Hyperplasia whereas Cyclin D3 Expression Results Only in Epidermal Hyperplasia

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

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