HIV-1 Tat: An update on transcriptional and non-transcriptional functions.

Over the past decades, much have been learned about HIV-1 virus and its molecular strategies for pathogenesis. However, HIV-1 still remains an enigmatic virus, particularly because of its unique proteins. Establishment of latency and reactivation is still a puzzling question and various temporal and spatial dynamics between HIV-1 proteins itself have given us new way of thinking about its pathogenesis. HIV-1 replication depends on Tat which is a small unstructured protein and subjected to various post-translational modifications for its myriad of functions. HIV-1 Tat protein modulates the functions of various strategic cellular pathways like proteasomal machinery and inflammatory pathways to aid in HIV-1 pathogenesis. Many of the recent findings have shown that Tat is associated with exosomes, cleared from HIV-1 infected cells through its degradation by diverse routes ranging from lysosomal to proteasomal pathways. HIV-1 Tat was also found to be associated with other HIV-1 proteins including Vpr, Nef, Nucleocapsid (NC) and Rev. Interaction of Tat with Vpr and Nef increases its transactivation function, whereas, interaction of Tat with NC or Rev leads to Tat protein degradation and hence suppression of Tat functions. Research in the recent years has established that Tat is not only important for HIV-1 promoter transactivation and virus replication but also modulating multiple cellular and molecular functions leading to HIV-1 pathogenicity. In this review we discussed various transcriptional and non-transcriptional HIV-1 Tat functions which modulate host cell metabolism during HIV-1 pathogenesis.

Constitutive activation and overexpression of NF-κB/c-Rel in conjunction with p50 contribute to aggressive tongue tumorigenesis.

Tongue squamous cell carcinoma (TSCC) is a most aggressive head and neck cancer often associated with a poor survival rate. Yet, it always shows better prognosis in presence of HPV16 infection. NF-κB plays a pivotal role in carcinogenesis and chemo-radio resistance of cancer but its role in tongue cancer is not yet explored. In this study, a total of hundred tongue tissue biopsies comprising precancer, cancer and adjacent normal controls including two tongue cancer cell lines (HPV+/-ve) were employed to examine expression and transactivation of NF-κB proteins, their silencing by siRNA and invasion assays to understand their contributions in tongue carcinogenesis. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tumors (78.5%). Increased DNA binding activity and differential expression of NF-κB proteins was observed with p50 and c-Rel being the two major DNA binding partners forming the functional NF-κB complex that increased as a function of severity of lesions in both HPV+/-ve tumors but selective participation of p65 in HPV16+ve TSCCs induced well differentiation of tumors resulting in better prognosis. siRNA treatment against c-Rel or Fra-2 led to upregulation of p27 but strong inhibition of c-Rel, c-Jun, c-myc, HPVE6/E7 and Fra-2 which is exclusively overexpressed in HPV-ve aggressive tumors. In conclusion, selective participation of c-Rel with p50 that in cross-talk with AP-1/Fra-2 induced poor differentiation and aggressive tumorigenesis mainly in HPV-ve smokers while HPV infection induced expression of p65 and p27 leading to well differentiation and better prognosis preferably in non-smoking TSCC patients.

Cervical cancer stem cells manifest radioresistance: Association with upregulated AP-1 activity.

Transcription factor AP-1 plays a central role in HPV-mediated cervical carcinogenesis. AP-1 has also been implicated in chemo-radio-resistance but the mechanism(s) remained unexplored. In the present study, cervical cancer stem-like cells (CaCxSLCs) isolated and enriched from cervical cancer cell lines SiHa and C33a demonstrated an elevated AP-1 DNA-binding activity in comparison to non-stem cervical cancer cells. Upon UV-irradiation, CaCxSLCs showed a UV exposure duration-dependent higher proliferation and highly increased AP-1 activity whereas it was completely abolished in non-stem cancer cells. CaCxSLCs also showed differential overexpression of c-Fos and c-Jun at transcript as well as in protein level. The loss of AP-1 activity and expression was accompanied by decrease in cell viability and proliferation in UV-irradiated non-stem cancer cells. Interestingly, CaCxSLCs treated with curcumin prior to UV-irradiation abolished AP-1 activity and a concomitant reduction in SP cells leading to abrogation of sphere forming ability, loss of proliferation, induction of apoptosis and the cells were poorly tumorigenic. The curcumin pre-treatment abolished the expression of c-Fos and c-Jun but upregulated Fra-1 expression in UV-irradiated CaCxSLCs. Thus, the study suggests a critical role of AP-1 protein in the manifestation of radioresistance but targeting with curcumin helps in radiosensitizing CaCxSLCs through upregulation of Fra-1.

Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer.

Tongue squamous cell carcinoma (TSCC) is most aggressive head and neck cancer often associated with HR-HPV infection. The role of AP-1 which is an essential regulator of HPV oncogene expression and tumorigenesis is not reported in tongue cancer. One hundred tongue tissue biopsies comprising precancer, cancer and adjacent controls including two tongue cancer cell lines were employed to study the role of HPV infection and AP-1 family proteins. An exclusive prevalence (28%) of HR-HPV type 16 was observed mainly in well differentiated tongue carcinomas (78.5%). A higher expression and DNA binding activity of AP-1 was observed in tongue tumors and cancer cell lines with c-Fos and Fra-2 as the major binding partners forming the functional AP-1 complex but c-Jun participated only in HPV negative and poorly differentiated carcinoma. Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated. The binding and expression of c-Fos/Fra-2 increased as a function of severity of tongue lesions, yet selective participation of c-Jun appears to promote poor differentiation and aggressive tumorigenesis only in HPV negative cases while HPV infection leads to well differentiation and better prognosis preferably in nonsmokers.

Association between lipoprotein(a) levels, apo(a) isoforms and family history of premature CAD in young Asian Indians.

OBJECTIVES: The purpose of this study was to explore the association between lipoprotein (a) [Lp(a)] levels, apo(a) isoforms and family history of premature coronary artery disease (CAD) in young Asian Indians. DESIGN AND METHODS: 220 patients (age <40 years) with angiographic evidence of CAD and 160 age matched healthy controls were enrolled for the study. Thirty one percent of the patients and 17% of the controls had positive family history (PFH) of premature CAD. Plasma Lp(a) levels were determined by ELISA and apo(a) isoform size was determined using high-resolution immunoblotting method. RESULTS: Median plasma Lp(a) levels were 2.5 times higher in patients as compared to controls (30 mg/dL vs 12.7 mg/dL; p<0.05). The patient group having a heterozygous apo(a) isoform pattern showed higher Lp(a) levels as compared to the homozygous group (44.0+/-38.7 vs 28.0+/-26.4 mg/dL; p<0.001). Further low molecular weight apo(a) isoforms (LMW; <22 KIV repeats) were prevalent among CAD patients with PFH as compared to negative family history (62% vs 14%, p<0.05) and this group had the highest Lp(a) levels. Stepwise regression analysis showed that Lp(a) levels and not the apo(a) isoform size, entered the model as significant independent predictors of CAD in young Asian Indians. CONCLUSIONS: This study suggests that elevated Lp(a) levels confer genetic predisposition to CAD in young Asian Indians. Thus determination of Lp(a) levels along with other risk factors should be used to assess overall risk for CAD in this ethnic group.