A large number of human and experimental cancers display genetic alterations that activate G1-control kinases (CDK4 and CDK6). In this process, aberrant levels""""""""ofD-type cyclins provide a growth advantage over normal cells. Whereas a role for cyclin D1 and D2 in cell proliferation have been established, recent data suggests that cyclin D3 (eye D3) plays additional roles in differentiation and growth arrest. This data correlates well with our preliminary results suggesting a role of eye D3 as a negative regulator of keratinocyte proliferation. Notably, overexpression of this cyclin results in inhibition of tumor development and decreased malignant progression to squamous cell carcinomas (SCC). Analysis of primary keratinocytes shows that overexpression of eye D3 results in strong reduction of the eye D2 protein levels, whereas elevated levels of eye D2 was observed in eye D3 null mice. Thus, we have hypothesized that eye D3 negatively regulate keratinocyte proliferation through a posttranslational mechanism downregulating eye D2. Supporting this hypothesis, cell lines derived from keratinocytes, papillomas and SCC, showed increased eye D3 stability in all but the SCC cell lines, whereas cell lines derived from SCC showed elevated stability of eye D1 suggesting that these two cyclins play opposing roles. To determine the potential application of D-type cyclins as target for therapeutic intervention it is essential to understand the role of each member. The work performed for this application has led to a number of relevant questions related to the roles of D-type cyclins in neoplastic development and epidermal homeostasis. However, in order to remain focused, we will concentrate on the role of eye D3 and eye D2 in tumorigenesis. Based on the preliminary results obtained for this application, we proposed two hypotheses: 1- Cyc D3 expression inhibits tumorigenesis through a posttranslational mechanism that results in decreased levels of eye D2 changing the proliferative capacity of epidermal cells. 2- Cyc D3 expression inhibits carcinogenesis by positive regulation of the differentiation process. In order to investigate these hypotheses, we propose the following specific aims: SA 1: To determine the effect of unbalanced expression of D-type cyclins in tumorigenesis. SA 2: To determine the posttranslational mechanism that regulates the levels of cyclin D2. SA 3: To determine the role of cyclin D3/CDK6 complexes in normal and neoplastic proliferation, and keratinocyte differentiation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Ogunbiyi, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
North Carolina State University Raleigh
Anatomy/Cell Biology
Schools of Veterinary Medicine
United States
Zip Code
Kim, Sun Hye; Sistrunk, Christopher; Miliani de Marval, Paula L et al. (2017) Characterization of hair-follicle side population cells in mouse epidermis and skin tumors. Oncol Lett 14:6497-6504
de Marval, Paula L Miliani; Kim, Sun Hye; Rodriguez-Puebla, Marcelo L (2014) Isolation and characterization of a stem cell side-population from mouse hair follicles. Methods Mol Biol 1195:259-68
Sistrunk, Christopher; Kim, Sun Hye; Wang, Xian et al. (2013) Skp2 deficiency inhibits chemical skin tumorigenesis independent of p27(Kip1) accumulation. Am J Pathol 182:1854-64
Wang, Xian; Sistrunk, Christopher; Miliani de Marval, Paula L et al. (2012) Combined effect of cyclin D3 expression and abrogation of cyclin D1 prevent mouse skin tumor development. Cell Cycle 11:335-42
Wang, Xian; Sistrunk, Christopher; Rodriguez-Puebla, Marcelo L (2011) Unexpected reduction of skin tumorigenesis on expression of cyclin-dependent kinase 6 in mouse epidermis. Am J Pathol 178:345-54
Sistrunk, Christopher; Macias, Everardo; Nakayama, Keiichi et al. (2011) Skp2 is necessary for Myc-induced keratinocyte proliferation but dispensable for Myc oncogenic activity in the oral epithelium. Am J Pathol 178:2470-7
Rojas, Paola; Benavides, Fernando; Blando, Jorge et al. (2009) Enhanced skin carcinogenesis and lack of thymus hyperplasia in transgenic mice expressing human cyclin D1b (CCND1b). Mol Carcinog 48:508-16
Patil, Mohini A; Lee, Susie A; Macias, Everardo et al. (2009) Role of cyclin D1 as a mediator of c-Met- and beta-catenin-induced hepatocarcinogenesis. Cancer Res 69:253-61
Macias, Everardo; Miliani de Marval, Paula L; Senderowicz, Adrian et al. (2008) Expression of CDK4 or CDK2 in mouse oral cavity is retained in adult pituitary with distinct effects on tumorigenesis. Cancer Res 68:162-71
Macias, Everardo; Miliani de Marval, Paula L; De Siervi, Adriana et al. (2008) CDK2 activation in mouse epidermis induces keratinocyte proliferation but does not affect skin tumor development. Am J Pathol 173:526-35

Showing the most recent 10 out of 12 publications