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Article ; Online: CDK4 has the ability to regulate Aurora B and Cenpp expression in mouse keratinocytes.

Lee, Sung Hyun / Rodriguez, Liliana R L / Majumdar, Rima / De Marval, Paula L Miliani / Rodriguez-Puebla, Marcelo L

2021 Volume 22, Issue 4, Page(s) 732

Abstract: Cyclin-dependent kinase 4 (CDK4) is a critical molecule that regulates key aspects of cell proliferation through phosphorylation of the retinoblastoma (Rb) family of proteins. In the last few years, it has been suggested that CDK4 plays alternative roles ...

Abstract	Cyclin-dependent kinase 4 (CDK4) is a critical molecule that regulates key aspects of cell proliferation through phosphorylation of the retinoblastoma (Rb) family of proteins. In the last few years, it has been suggested that CDK4 plays alternative roles in cell proliferation and tumorigenesis. The main aim of the present study was to define a novel CDK4 function as a transcriptional regulator of genes involved in chromosome segregation, contributing to the G
Language	English
Publishing date	2021-08-11
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2573196-8
ISSN	1792-1082 ; 1792-1074
ISSN (online)	1792-1082
ISSN	1792-1074
DOI	10.3892/ol.2021.12993
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Article: Characterization of hair-follicle side population cells in mouse epidermis and skin tumors.

Kim, Sun Hye / Sistrunk, Christopher / Miliani de Marval, Paula L / Rodriguez-Puebla, Marcelo L

Oncology letters

2017 Volume 14, Issue 6, Page(s) 6497–6504

Abstract: A subset of cells, termed side-population (SP), which have the ability to efflux Hoeschst 33342, have previously been demonstrated to act as a potential method to isolate stem cells. Numerous stem/progenitor cells have been localized in different regions ...

Abstract	A subset of cells, termed side-population (SP), which have the ability to efflux Hoeschst 33342, have previously been demonstrated to act as a potential method to isolate stem cells. Numerous stem/progenitor cells have been localized in different regions of the mouse hair follicle (HF). The present study identified a SP in the mouse HF expressing the ABCG2 transporter and MTS24 surface marker. These cells are restricted to the upper isthmus of the HF and have previously been described as progenitor cells. Consistent with their SP characteristic, they demonstrated elevated expression of ABCG2 transporter, which participates in the dye efflux. Analysis of tumor epidermal cell lines revealed a correlation between the number of SP keratinocytes and the grade of malignancy, suggesting that the SP may play a role in malignant progression. Consistent with this idea, the present study observed an increased number of cells expressing ABCG2 and MTS24 in chemically induced skin tumors and skin tumor cell lines. This SP does not express the CD34 surface marker detected in the multipotent stem cells of the bulge region of the HF, which have been defined as tumor initiation cells. The present study concluded that a SP with properties of progenitor cells is localized in the upper isthmus of the HF and is important in mouse skin tumor progression.
Language	English
Publishing date	2017-09-25
Publishing country	Greece
Document type	Journal Article
ZDB-ID	2573196-8
ISSN	1792-1082 ; 1792-1074
ISSN (online)	1792-1082
ISSN	1792-1074
DOI	10.3892/ol.2017.7048
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Article ; Online: CDK2 activation in mouse epidermis induces keratinocyte proliferation but does not affect skin tumor development.

Macias, Everardo / Miliani de Marval, Paula L / De Siervi, Adriana / Conti, Claudio J / Senderowicz, Adrian M / Rodriguez-Puebla, Marcelo L

The American journal of pathology

2008 Volume 173, Issue 2, Page(s) 526–535

Abstract: It has been widely assumed that elevated CDK2 kinase activity plays a contributory role in tumorigenesis. We have previously shown that mice overexpressing CDK4 under control of the keratin 5 promoter (K5CDK4 mice) develop epidermal hyperplasia and ... ...

Abstract	It has been widely assumed that elevated CDK2 kinase activity plays a contributory role in tumorigenesis. We have previously shown that mice overexpressing CDK4 under control of the keratin 5 promoter (K5CDK4 mice) develop epidermal hyperplasia and increased susceptibility to squamous cell carcinomas. In this model, CDK4 overexpression results in increased CDK2 activity associated with the noncatalytic function of CDK4, sequestration of p21(Cip1) and p27(Kip1). Furthermore, we have shown that ablation of Cdk2 reduces Ras-Cdk4 tumorigenesis, suggesting that increased CDK2 activity plays an important role in Ras-mediated tumorigenesis. To investigate this hypothesis, we generated two transgenic mouse models of elevated CDK2 kinase activity, K5Cdk2 and K5Cdk4(D158N) mice. The D158N mutation blocks CDK4 kinase activity without interfering with its binding capability. CDK2 activation via overexpression of CDK4(D158N), but not of CDK2, resulted in epidermal hyperplasia. We observed elevated levels of p21(Cip1) in K5Cdk2, but not in K5Cdk4(D158N), epidermis, suggesting that CDK2 overexpression elicits a p21(Cip1) response to maintain keratinocyte homeostasis. Surprisingly, we found that neither CDK2 overexpression nor the indirect activation of CDK2 enhanced skin tumor development. Thus, although the indirect activation of CDK2 is sufficient to induce keratinocyte hyperproliferation, activation of CDK2 alone does not induce malignant progression in Ras-mediated tumorigenesis.
MeSH term(s)	9,10-Dimethyl-1,2-benzanthracene ; Animals ; Cell Proliferation ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Cyclin-Dependent Kinase 2/genetics ; Cyclin-Dependent Kinase 2/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Enzyme Activation ; Epidermis/enzymology ; Epidermis/pathology ; Keratinocytes/enzymology ; Keratinocytes/pathology ; Mice ; Mice, Transgenic ; Mutation ; Skin Neoplasms/chemically induced ; Skin Neoplasms/enzymology ; Skin Neoplasms/pathology
Chemical Substances	Cdkn1a protein, mouse ; Cdkn1b protein, mouse ; Cyclin-Dependent Kinase Inhibitor p21 ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; 9,10-Dimethyl-1,2-benzanthracene (57-97-6) ; Cdk2 protein, mouse (EC 2.7.11.22) ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22)
Language	English
Publishing date	2008-07-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.2353/ajpath.2008.071124
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Article ; Online: The RP-Mdm2-p53 pathway and tumorigenesis.

Miliani de Marval, Paula L / Zhang, Yanping

Oncotarget

2011 Volume 2, Issue 3, Page(s) 234–238

Abstract: The dynamic processes of cell growth and division are under constant surveillance. As one of the primary "gatekeepers" of the cell, the p53 tumor suppressor plays a major role in sensing and responding to a variety of stressors to maintain cellular ... ...

Abstract	The dynamic processes of cell growth and division are under constant surveillance. As one of the primary "gatekeepers" of the cell, the p53 tumor suppressor plays a major role in sensing and responding to a variety of stressors to maintain cellular homeostasis. Recent studies have shown that inhibition of ribosomal biogenesis can activate p53 through ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity. Mutations in Mdm2 that disrupt RP binding have been detected in human cancers; however, the physiological significance of the RP-Mdm2 interaction is not completely understood. We generated mice carrying a single cysteine-to-phenylalanine substitution in the central zinc finger of Mdm2 (Mdm2C305F) that disrupts Mdm2's binding to RPL11 and RPL5. Despite being developmentally normal and maintaining an intact p53 response to DNA damage, the Mdm2C305F mice demonstrate a diminished p53 response to perturbations in ribosomal biogenesis, providing the first in vivo evidence for an RP-Mdm2-p53 signaling pathway. Here we review some recent studies about RP-Mdm2-p53 signaling and speculate on the relevance of this pathway to human cancer.
MeSH term(s)	Animals ; Cell Cycle/physiology ; Cell Transformation, Neoplastic/metabolism ; Genes, p53 ; Humans ; Mice ; Proto-Oncogene Proteins c-mdm2/genetics ; Proto-Oncogene Proteins c-mdm2/metabolism ; Ribosomal Proteins/genetics ; Ribosomal Proteins/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Zinc Fingers
Chemical Substances	Ribosomal Proteins ; Tumor Suppressor Protein p53 ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
Language	English
Publishing date	2011-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.228
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Article ; Online: Isolation and characterization of a stem cell side-population from mouse hair follicles.

Miliani de Marval, Paula L / Kim, Sun Hye / Rodriguez-Puebla, Marcelo L

Methods in molecular biology (Clifton, N.J.)

2014 Volume 1195, Page(s) 259–268

Abstract: The mouse skin is composed of at least three differentiating epithelial compartments: the epidermis, the hair follicle, and the associated glands such as the sebaceous glands. Proliferation of these epithelial cells takes place in the keratinocytes' ... ...

Abstract	The mouse skin is composed of at least three differentiating epithelial compartments: the epidermis, the hair follicle, and the associated glands such as the sebaceous glands. Proliferation of these epithelial cells takes place in the keratinocytes' layer or basal cell layer; in the periphery of the sebaceous gland (the basal layer of the gland) and in specific cell compartments around the hair follicle. In mouse skin, an epithelial stem cell population is thought to localize to the bulge region of the hair follicle, a segment that does not undergo regression during the hair cycle. In addition, several other putative stem cells and/or progenitors have been identified in different regions of the hair follicle. Using the Hoeschst exclusion technique, originally described in the hematopoietic system, it has been possible to isolate a mouse keratinocyte cell population with characteristics of stem cells (side-population, SP). One of the main features of these SP is their ability to efflux antimitotic drugs as well as some specific dyes. This characteristic allows for SP cells to be isolated based upon their capacity to efflux the dye Hoechst 33342, through a mechanism driven by a membrane transporter, the breast cancer resistance protein (BCRP1/ABCG2). In this chapter, we described the isolation of SP stem cells from adult mouse hair follicles utilizing the Hoeschst exclusion technique by flow cytometry analysis.
MeSH term(s)	ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters/genetics ; Animals ; Flow Cytometry/methods ; Gene Expression Regulation ; Hair Follicle/cytology ; Mice ; Side-Population Cells/cytology ; Side-Population Cells/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; Abcg2 protein, mouse
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/7651_2013_61
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Article ; Online: Combined effect of cyclin D3 expression and abrogation of cyclin D1 prevent mouse skin tumor development.

Wang, Xian / Sistrunk, Christopher / Miliani de Marval, Paula L / Kim, Yongbaek / Rodriguez-Puebla, Marcelo L

Cell cycle (Georgetown, Tex.)

2012 Volume 11, Issue 2, Page(s) 335–342

Abstract: We have previously demonstrated that ras-mediated skin tumorigenesis depends on signaling pathways that act preferentially through cyclin D1 and D2. Interestingly, the expression of cyclin D3 inhibits skin tumor development, an observation that conflicts ...

Abstract	We have previously demonstrated that ras-mediated skin tumorigenesis depends on signaling pathways that act preferentially through cyclin D1 and D2. Interestingly, the expression of cyclin D3 inhibits skin tumor development, an observation that conflicts with the oncogenic role of D-type cyclins in the mouse epidermis. Here, we show that simultaneous up and downregulation of particular members of the D-type cyclin family is a valuable approach to reduce skin tumorigenesis. We developed the K5D3/cyclin D1(-/-) compound mouse, which overexpresses cyclin D3 but lacks expression of cyclin D1 in the skin. Similar to K5D3 transgenic mice, keratinocytes from K5D3/cyclin D1(-/-) compound mice show a significant reduction of cyclin D2 levels. Therefore, this model allows us to determine the effect of cyclin D3 expression when combined with reduced or absent expression of the remaining two members of the D-type cyclin family in mouse epidermis. Our data show that induced expression of cyclin D3 compensates for the reduced level of cyclin D1 and D2, resulting in normal keratinocyte proliferation. However, simultaneous ablation of cyclin D1 and downregulation of cyclin D2 via cyclin D3 expression resulted in a robust reduction in ras-mediated skin tumorigenesis. We conclude that modulation of the levels of particular members of the D-type cyclin family could be useful to inhibit tumor development and, in particular, ras-mediated tumorigenesis.
MeSH term(s)	9,10-Dimethyl-1,2-benzanthracene ; Animals ; Carcinoma, Squamous Cell/chemically induced ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Proliferation ; Cell Transformation, Neoplastic ; Cyclin D1/genetics ; Cyclin D1/metabolism ; Cyclin D2/metabolism ; Cyclin D3/genetics ; Cyclin D3/metabolism ; Gene Expression Regulation ; Mice ; Mice, Transgenic ; Oncogene Protein p21(ras)/genetics ; Papilloma/chemically induced ; Papilloma/metabolism ; Papilloma/pathology ; Skin/pathology ; Skin Neoplasms/chemically induced ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Tumor Burden
Chemical Substances	Ccnd1 protein, mouse ; Ccnd2 protein, mouse ; Ccnd3 protein, mouse ; Cyclin D2 ; Cyclin D3 ; Cyclin D1 (136601-57-5) ; 9,10-Dimethyl-1,2-benzanthracene (57-97-6) ; Oncogene Protein p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2012-01-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.11.2.18774
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Article ; Online: Expression of CDK4 or CDK2 in mouse oral cavity is retained in adult pituitary with distinct effects on tumorigenesis.

Macias, Everardo / Miliani de Marval, Paula L / Senderowicz, Adrian / Cullen, John / Rodriguez-Puebla, Marcelo L

Cancer research

2008 Volume 68, Issue 1, Page(s) 162–171

Abstract: The keratin 5 (K5) promoter drives transgenic expression to the basal cell layer of stratified epithelia. Surprisingly, analysis of K5CDK4 and K5CDK2 transgenic mouse embryos showed CDK4 and CDK2 expression not only in the expected tissues, but also in ... ...

Abstract	The keratin 5 (K5) promoter drives transgenic expression to the basal cell layer of stratified epithelia. Surprisingly, analysis of K5CDK4 and K5CDK2 transgenic mouse embryos showed CDK4 and CDK2 expression not only in the expected tissues, but also in the adenohypophysis. This organ is derived from an upwards growth of the primitive oropharynx, a K5-expressing tissue. We show that transgenic expression of CDKs in the embryonic oral ectoderm is specifically retained in undifferentiated cells from the pars intermedia of the adenohypophysis. Interestingly, we found that K5CDK4 mice show a decreased number of pituitary stem cells, even though CDK4 is not expressed in the stem cells but in transit-amplifying (TA)-like cells. Interestingly, CDK4-expressing cells, but not CDK2-expressing cells, strongly synergize with lack of p27(Kip1) to generate pituitary carcinomas that appear with shortened latency and are drastically more aggressive than those arising in p27(-/-) mice. Thus, we show that deregulation of CDK expression in the primitive oral epithelium plays a unique function, providing a selective advantage that gives rise to transgene-positive TA-like pituitary cells. Furthermore, retention of CDK4 in these TA-like pituitary cells synergizes with loss of p27(Kip1) to induce pituitary adenocarcinomas. This model suggests that forced expression of CDK4 sensitizes cells and synergizes with a second change resulting in tumor development.
MeSH term(s)	Animals ; Cell Count ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cyclin-Dependent Kinase 2/analysis ; Cyclin-Dependent Kinase 2/genetics ; Cyclin-Dependent Kinase 2/metabolism ; Cyclin-Dependent Kinase 4/analysis ; Cyclin-Dependent Kinase 4/genetics ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/genetics ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Humans ; Mice ; Mice, Transgenic ; Mouth/embryology ; Mouth/enzymology ; Pituitary Gland/enzymology ; Pituitary Neoplasms/enzymology ; Pituitary Neoplasms/genetics ; Promoter Regions, Genetic ; Stem Cells
Chemical Substances	Cdkn1b protein, mouse ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22)
Language	English
Publishing date	2008-01-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-07-2461
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Article ; Online: Deep sequencing shows multiple oligouridylations are required for 3' to 5' degradation of histone mRNAs on polyribosomes.

Slevin, Michael K / Meaux, Stacie / Welch, Joshua D / Bigler, Rebecca / Miliani de Marval, Paula L / Su, Wei / Rhoads, Robert E / Prins, Jan F / Marzluff, William F

Molecular cell

2014 Volume 53, Issue 6, Page(s) 1020–1030

Abstract: Histone mRNAs are rapidly degraded when DNA replication is inhibited during S phase with degradation initiating with oligouridylation of the stem loop at the 3' end. We developed a customized RNA sequencing strategy to identify the 3' termini of ... ...

Abstract	Histone mRNAs are rapidly degraded when DNA replication is inhibited during S phase with degradation initiating with oligouridylation of the stem loop at the 3' end. We developed a customized RNA sequencing strategy to identify the 3' termini of degradation intermediates of histone mRNAs. Using this strategy, we identified two types of oligouridylated degradation intermediates: RNAs ending at different sites of the 3' side of the stem loop that resulted from initial degradation by 3'hExo and intermediates near the stop codon and within the coding region. Sequencing of polyribosomal histone mRNAs revealed that degradation initiates and proceeds 3' to 5' on translating mRNA and that many intermediates are capped. Knockdown of the exosome-associated exonuclease PM/Scl-100, but not the Dis3L2 exonuclease, slows histone mRNA degradation consistent with 3' to 5' degradation by the exosome containing PM/Scl-100. Knockdown of No-go decay factors also slowed histone mRNA degradation, suggesting a role in removing ribosomes from partially degraded mRNAs.
MeSH term(s)	3' Untranslated Regions ; Base Sequence ; Codon ; Exoribonucleases/genetics ; Exoribonucleases/metabolism ; Exosome Multienzyme Ribonuclease Complex/genetics ; Exosome Multienzyme Ribonuclease Complex/metabolism ; Gene Expression Regulation, Developmental ; Gene Library ; HeLa Cells ; Histones/genetics ; Histones/metabolism ; Humans ; Jurkat Cells ; Molecular Sequence Data ; Nucleic Acid Conformation ; Open Reading Frames ; Polyribosomes/genetics ; Polyribosomes/metabolism ; RNA Stability ; S Phase/genetics ; Sequence Analysis, RNA ; Signal Transduction ; Uridine/metabolism
Chemical Substances	3' Untranslated Regions ; Codon ; Histones ; DIS3L2 protein, human (EC 3.1.-) ; Exoribonucleases (EC 3.1.-) ; Exosome Multienzyme Ribonuclease Complex (EC 3.1.-) ; EXOSC10 protein, human (EC 3.1.13.-) ; Uridine (WHI7HQ7H85)
Language	English
Publishing date	2014-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2014.02.027
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Article: Enhanced malignant tumorigenesis in Cdk4 transgenic mice.

Miliani de Marval, Paula L / Macias, Everardo / Conti, Claudio J / Rodriguez-Puebla, Marcelo L

Oncogene

2004 Volume 23, Issue 10, Page(s) 1863–1873

Abstract: In a previous study, we reported that overexpression of cyclin-dependent kinase-4 (CDK4) in mouse epidermis results in epidermal hyperplasia, hypertrophy and severe dermal fibrosis. In this study, we have investigated the susceptibility to skin tumor ... ...

Abstract	In a previous study, we reported that overexpression of cyclin-dependent kinase-4 (CDK4) in mouse epidermis results in epidermal hyperplasia, hypertrophy and severe dermal fibrosis. In this study, we have investigated the susceptibility to skin tumor formation by forced expression of CDK4. Skin tumors from transgenic mice showed a dramatic increase in the rate of malignant progression to squamous cell carcinomas (SCC) in an initiation-promotion protocol. Histopathological analysis of papillomas from transgenic mice showed an elevated number of premalignant lesions characterized by dysplasia and marked atypia. Interestingly, transgenic mice also developed tumors in initiated but not promoted skin, demonstrating that CDK4 replaced the action of tumor promoters. These results suggest that expression of cyclin D1 upon ras activation synergizes with CDK4 overexpression. However, cyclin D1 transgenic mice and double transgenic mice for cyclin D1 and CDK4 did not show increased malignant progression in comparison to CDK4 transgenic mice. Biochemical analysis of tumors showed that CDK4 sequesters the CDK2 inhibitors p27Kip1 and p21Cip1, suggesting that indirect activation of CDK2 plays an important role in tumor development. These results indicate that, contrary to the general assumption, the catalytic subunit, CDK4, has higher oncogenic activity than cyclin D1, revealing a potential use of CDK4 as therapeutic target.
MeSH term(s)	Animals ; Carcinoma/genetics ; Carcinoma/pathology ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/pathology ; Cyclin-Dependent Kinase 4 ; Cyclin-Dependent Kinases/genetics ; Humans ; Mice ; Mice, Transgenic ; Papilloma/genetics ; Papilloma/pathology ; Proto-Oncogene Proteins ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology
Chemical Substances	Proto-Oncogene Proteins ; CDK4 protein, human (EC 2.7.11.22) ; Cdk4 protein, mouse (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; Cyclin-Dependent Kinases (EC 2.7.11.22)
Language	English
Publishing date	2004-03-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	639046-8
ISSN	1476-5594 ; 0950-9232
ISSN (online)	1476-5594
ISSN	0950-9232
DOI	10.1038/sj.onc.1207309
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Article: Cdk2 deficiency decreases ras/CDK4-dependent malignant progression, but not myc-induced tumorigenesis.

Macias, Everardo / Kim, Yongbaek / Miliani de Marval, Paula L / Klein-Szanto, Andres / Rodriguez-Puebla, Marcelo L

Cancer research

2007 Volume 67, Issue 20, Page(s) 9713–9720

Abstract: We have previously shown that forced expression of CDK4 in mouse skin (K5CDK4 mice) results in increased susceptibility to squamous cell carcinoma (SCC) development in a chemical carcinogenesis protocol. This protocol induces skin papilloma development, ... ...

Abstract	We have previously shown that forced expression of CDK4 in mouse skin (K5CDK4 mice) results in increased susceptibility to squamous cell carcinoma (SCC) development in a chemical carcinogenesis protocol. This protocol induces skin papilloma development, causing a selection of cells bearing activating Ha-ras mutations. We have also shown that myc-induced epidermal proliferation and oral tumorigenesis (K5Myc mice) depends on CDK4 expression. Biochemical analysis of K5CDK4 and K5Myc epidermis as well as skin tumors showed that keratinocyte proliferation is mediated by CDK4 sequestration of p27Kip1 and p21Cip1, and activation of CDK2. Here, we studied the role of CDK2 in epithelial tumorigenesis. In normal skin, loss of CDK2 rescues CDK4-induced, but not myc-induced epidermal hyperproliferation. Ablation of CDK2 in K5CDK4 mice results in decreased incidences and multiplicity of skin tumors as well as malignant progression to SCC. Histopathologic analysis showed that K5CDK4 tumors are drastically more aggressive than K5CDK4/CDK2-/- tumors. On the other hand, we show that CDK2 is dispensable for myc-induced tumorigenesis. In contrast to our previous report of K5Myc/CDK4-/-, K5Myc/CDK2-/- mice developed oral tumors with the same frequency as K5Myc mice. Overall, we have established that ras-induced tumors are more susceptible to CDK2 ablation than myc-induced tumors, suggesting that the efficacy of targeting CDK2 in tumor development and malignant progression is dependent on the oncogenic pathway involved.
MeSH term(s)	Animals ; Carcinogens ; Carcinoma, Squamous Cell/enzymology ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Cyclin-Dependent Kinase 2/deficiency ; Cyclin-Dependent Kinase 2/metabolism ; Cyclin-Dependent Kinase 4/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Disease Progression ; Enzyme Activation ; Female ; Male ; Mice ; Mice, Transgenic ; Proto-Oncogene Proteins c-myc/biosynthesis ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Skin Neoplasms/chemically induced ; Skin Neoplasms/enzymology ; Skin Neoplasms/pathology ; Tetradecanoylphorbol Acetate ; ras Proteins/metabolism
Chemical Substances	Carcinogens ; Cdkn1a protein, mouse ; Cdkn1b protein, mouse ; Cyclin-Dependent Kinase Inhibitor p21 ; Myc protein, mouse ; Proto-Oncogene Proteins c-myc ; Cyclin-Dependent Kinase Inhibitor p27 (147604-94-2) ; Cdk2 protein, mouse (EC 2.7.11.22) ; Cdk4 protein, mouse (EC 2.7.11.22) ; Cyclin-Dependent Kinase 2 (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) ; ras Proteins (EC 3.6.5.2) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
Language	English
Publishing date	2007-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-07-2119
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