Pharmacy and Pharmaceutical Sciences Commons^™

Design And Development Of A Novel Class Of Cell Cycle Cdk Inhibitors Targeting The Cyclin Binding Groove Utilizing The Replace Strategy, Padmavathy Nandha Premnath

Theses and Dissertations

Inhibition of CDK2 activity in G1 and S phases of the cell cycle can promote selective apoptosis of cancer cells through the E2F1 pathway. Currently available CDK inhibitors target the ATP binding pocket and result in lack of specificity for the cell cycle vs. the transcriptional CDKs. It has been shown that a peptide HAKRRLIF derived from the tumor suppressor p21 binds to the cyclin binding groove (CBG) and selectively inhibits cell cycle CDKs (CDK2/Cyclin A, CDK2/Cyclin E and CDK4/Cyclin D). The CBG is unique to cell cycle CDKs hence targeting this site avoids the inhibition of transcriptional CDKs can …

Six1 Overexpression Promotes Epithelial– Mesenchymal Transition And Malignant Progression In Models Of Cervical And Colon Cancer, Hanwen Xu

Theses and Dissertations

Inappropriate expression of embryonic genes, particularly homeodomain transcription factors, contributes to tumorigenesis and tumor progression. The overexpression of Six1, a member of the Six family of homeodomain transcription factors, has been found in various human cancers, and is associated with tumor progression and metastasis. We have previously determined that the expression of SIX1 mRNA increased during in vitro progression of human papillomavirus type 16 (HPV16)- immortalized human keratinocytes (HKc/HPV16) toward a differentiation-resistant (HKc/DR) phenotype. However, the mechanism(s) of how Six1 promotes HPV16- mediated transformation remain unknown. In this study, we explored the role of Six1 at early stages and late …

Investigation Of The Response And Repair Of Replication, Kathryn Brady

Theses and Dissertations

When a mammalian cell suffers DNA damage, DNA damage signaling responses and repair pathways are invoked. The phosphorylation of histone variant H2AX (γH2AX) and of replication protein A (pRPA) are two well-documented damage signals, marking double strand breaks and stalled replication forks, respectively. Inhibitors of thymidylate synthase (TS) and ribonucleotide reductase (RNR) are chemotherapeutics that act by depriving cells of the deoxynucleotides necessary for DNA synthesis, which causes damage. The response and repair pathways activated by these chemotherapeutics have been studied for a number of years but there remain unanswered questions as to how cancer cells perceive this damage, the …

Effects Of Hiv-1 Tat Protein On Structure, Function And Trafficking Of The Dopamine Transporter, Narasimha Murty Midde

Theses and Dissertations

The alarming rise in HIV-1 associated neurocognitive disorder (HAND) is, at least in part, associated with HIV-1 viral proteins shed from infected macrophages, including transactivator of transcription (Tat) despite the success of anti-retroviral therapies. The dopamine (DA) system is greatly involved in the progression of HAND and is influenced by psychostimulants like cocaine. The DA transporter (DAT), a key regulator of neurocognitive functions, is a major molecular target for both Tat and cocaine. Our lab previously reported that exposure to Tat decreases DA uptake through allosteric regulation and alters cocaine binding sites in DAT.

In this research project the hypothesis …

Role Of Micro Rna 148/152 Family In Cancer Progression, Anusha Chaparala

Theses and Dissertations

Micro RNA are small single stranded RNA that regulate the expression of various genes. MiRNA guide the mRNA disintegrating RISC complex to the complimentary sequence in the target mRNA. Each micro RNA has multiple targets and can play a different biological role depending on the population of targets at the particular stage of the cell or a physiological state. Several miRNA show elevated or decreased levels of expression in various cancers because of their role in tumor initiation and progression. MiRNA belonging to mir148/152 family are examples of such MicroRNA. This family includes miR148a, miR148b and miR152. MiR148a and miR152 …