Only ~3% of the human genome encodes protein and the remaining 97% is referred to as noncoding DNA. Initially, much of the intergenic noncoding sequence was referred to as junk DNA as it was considered to have no function. However, many intergenic sequences can be transcribed into RNA. In fact, ~85% of the human genome is transcribed into RNA. RNAs that lack protein coding function are referred to as noncoding RNAs and of these the long noncoding RNAs (lncRNAs >200 nt) represent the majority. LncRNAs are one of the largest and most diverse classes of cellular transcripts with over 10,000 transcripts. Only a few lncRNAs have been studied to date but emerging evidence indicates lncRNAs have key roles in regulating gene expression and are associated with human diseases such as cancer, Alzheimer's and heart disease. It is critical to determine whether associations of lncRNAs with specific diseases are functionally significant and to develop mouse genetic models to define and characterize the function of lncRNAs in disease in vivo. Such studies could lead to development of prognostic markers and molecular targets for therapy. Given that the etiology of most chronic human diseases involves interactions with the environment, it is also important to determine if environmental factors can impact the expression, activity and function of lncRNAs to contribute to disease. Nonmelanoma skin cancer (NMSC) is the most common cancer in the US. The majority of NMSC is caused by UVB radiation from sunlight. p53 plays a key role in the response of skin keratinocytes to UVB- induced DNA damage by inducing cell cycle arrest and apoptosis. In NMSC, UVB-induced mutation of p53 allows keratinocytes upon successive UVB exposures to evade apoptosis and cell cycle arrest. These defects have a critical role in NMSC development. LincRNA-p21 is an lncRNA and a direct transcriptional target of p53 and is reported to induce apoptosis in mouse fibroblasts in culture. We reasoned that lincRNA-p21 could have a critical role in UVB-induced apoptosis in keratinocytes and its loss in the evasion of apoptosis and the pathogenesis of skin cancer. Our preliminary data show lincRNA-p21 is highly inducible by UVB and has a key role in UVB-induced apoptosis in keratinocytes. We plan to define the regulation and function of lincRNA-p21 in keratinocytes and to develop mouse genetic models to define the molecular function of lincRNA-p21 in controlling keratinocyte gene expression, apoptosis and skin cancer in response to UVB radiation. The central hypotheses are; i) lincRNA-p21 is induced by UVB in keratinocytes through a p53-dependent pathway to trigger apoptotic cell death and ii) lincRNA-p21 functions as a tumor suppressor in NMSC whereby the loss of lincRNA-p21 expression allows both mutant p53 and non-mutant p53 keratinocytes to evade UVB-induced apoptosis leading to skin cancer. If correct, these studies will reveal for the first time that; i) a lncRNA an function as a tumor suppressor in vivo in a mouse model, ii) an environmental factor can control the expression, activity and function of a lncRNA and iii) a lncRNA has a key role in an environmentally-induced disease.
RNAs that lack protein coding function are referred to as noncoding RNAs and of these the long noncoding RNAs (lncRNAs) represent the majority with over 10,000 different lncRNAs reported in the human genome. Only a few lncRNAs have been studied to date, but emerging evidence suggests they have a key role in regulating gene expression and are associated with human diseases such as cancer, Alzheimer's and heart disease. It is critical to define the function of lncRNAs in disease because such an understanding could allow for development of new prognostic markers, biomarkers for early cancer detection and molecular targets for therapy. Given that the etiology of most chronic diseases involves interactions with the environment, it is vital to understand if environmental factors impact the expression, activity and function of lncRNAs to contribute to disease as such an understanding could provide opportunities for disease prevention.
|Messenger, Zachary J; Hall, Jonathan R; Jima, Dereje D et al. (2018) C/EBP? deletion in oncogenic Ras skin tumors is a synthetic lethal event. Cell Death Dis 9:1054|