@article{patil_lee_macias_lam_xu_jones_ho_rodriguez-puebla_chen_2009, title={Robe of Cyclin D1 as a Mediator of c-Met- and beta-Catenin-Induced Hepatocarcinogenesis}, volume={69}, ISSN={["1538-7445"]}, DOI={10.1158/0008-5472.CAN-08-2514}, abstractNote={Abstract}, number={1}, journal={CANCER RESEARCH}, author={Patil, Mohini A. and Lee, Susie A. and Macias, Everardo and Lam, Ernest T. and Xu, Chuanrui and Jones, Kirk D. and Ho, Coral and Rodriguez-Puebla, Marcelo and Chen, Xin}, year={2009}, month={Jan}, pages={253–261} }
 @article{macias_marval_de siervi_conti_senderowicz_rodriguez-puebla_2008, title={CDK2 activation in mouse epidermis induces keratinocyte proliferation but does not affect skin tumor development}, volume={173}, ISSN={["1525-2191"]}, DOI={10.2353/ajpath.2008.071124}, abstractNote={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.}, number={2}, journal={AMERICAN JOURNAL OF PATHOLOGY}, author={Macias, Everardo and Marval, Paula L. Miliani and De Siervi, Adriana and Conti, Claudio J. and Senderowicz, Adrian M. and Rodriguez-Puebla, Marcelo L.}, year={2008}, month={Aug}, pages={526–535} }
 @article{macias_marva_senderowicz_cullen_rodriguez-puebla_2008, title={Expression of CDK4 or CDK2 in mouse oral cavity is retained in adult pituitary with distinct effects on tumorigenesis}, volume={68}, ISSN={["0008-5472"]}, DOI={10.1158/0008-5472.CAN-07-2461}, abstractNote={Abstract}, number={1}, journal={CANCER RESEARCH}, author={Macias, Everardo and Marva, Paula L. Miliani and Senderowicz, Adrian and Cullen, John and Rodriguez-Puebla, Marcelo L.}, year={2008}, month={Jan}, pages={162–171} }
 @article{macias_kim_marval_klein-szanto_rodriguez-puebla_2007, title={Cdk2 deficiency decreases ras/CDK4-dependent malignant progression, but not myc-induced tumorigenesis}, volume={67}, ISSN={["1538-7445"]}, DOI={10.1158/0008-5472.CAN-07-2119}, abstractNote={Abstract}, number={20}, journal={CANCER RESEARCH}, author={Macias, Everardo and Kim, Yongbaek and Marval, Paula L. Miliani and Klein-Szanto, Andres and Rodriguez-Puebla, Marcelo L.}, year={2007}, month={Oct}, pages={9713–9720} }
 @article{marval_macias_conti_rodriguez-puebla_2004, title={Enhanced malignant tumorigenesis in Cdk4 transgenic mice}, volume={23}, ISSN={["1476-5594"]}, DOI={10.1038/sj.onc.1207309}, abstractNote={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.}, number={10}, journal={ONCOGENE}, author={Marval, PLM and Macias, E and Conti, CJ and Rodriguez-Puebla, ML}, year={2004}, month={Mar}, pages={1863–1873} }
 @article{marval_macias_rounbehler_sicinski_kiyokawa_johnson_conti_rodriguez-puebla_2004, title={Lack of cyclin-dependent kinase 4 inhibits c-myc tumorigenic activities in epithelial tissues}, volume={24}, ISSN={["1098-5549"]}, DOI={10.1128/MCB.24.17.7538-7547.2004}, abstractNote={ABSTRACT The proto-oncogene c-myc encodes a transcription factor that is implicated in the regulation of cellular proliferation, differentiation, and apoptosis and that has also been found to be deregulated in several forms of human and experimental tumors. We have shown that forced expression of c-myc in epithelial tissues of transgenic mice (K5-Myc) resulted in keratinocyte hyperproliferation and the development of spontaneous tumors in the skin and oral cavity. Although a number of genes involved in cancer development are regulated by c-myc, the actual mechanisms leading to Myc-induced neoplasia are not known. Among the genes regulated by Myc is the cyclin-dependent kinase 4 (CDK4) gene. Interestingly, previous studies from our laboratory showed that the overexpression of CDK4 led to keratinocyte hyperproliferation, although no spontaneous tumor development was observed. Thus, we tested the hypothesis that CDK4 may be one of the critical downstream genes involved in Myc carcinogenesis. Our results showed that CDK4 inhibition in K5-Myc transgenic mice resulted in the complete inhibition of tumor development, suggesting that CDK4 is a critical mediator of tumor formation induced by deregulated Myc. Furthermore, a lack of CDK4 expression resulted in marked decreases in epidermal thickness and keratinocyte proliferation compared to the results obtained for K5-Myc littermates. Biochemical analysis of the K5-Myc epidermis showed that CDK4 mediates the proliferative activities of Myc by sequestering p21Cip1 and p27Kip1 and thereby indirectly activating CDK2 kinase activity. These results show that CDK4 mediates the proliferative and oncogenic activities of Myc in vivo through a mechanism that involves the sequestration of specific CDK inhibitors.}, number={17}, journal={MOLECULAR AND CELLULAR BIOLOGY}, author={Marval, PLM and Macias, E and Rounbehler, R and Sicinski, P and Kiyokawa, H and Johnson, DG and Conti, CJ and Rodriguez-Puebla, ML}, year={2004}, month={Sep}, pages={7538–7547} }