The high risk HPV16 L2 minor capsid protein has multiple transport signals that mediate its nucleocytoplasmic traffic

AbstractIn this study we examined the transport signals contributing to HPV16 L2 nucleocytoplasmic traffic using confocal microscopy analysis of enhanced green fluorescent protein—L2 (EGFP-L2) fusions expressed in HeLa cells. We confirmed that both nuclear localization signals (NLSs), the nNLS (1MRHKRSAKRTKR12) and cNLS (456RKRRKR461), previously characterized in vitro (Darshan et al., 2004), function independently in vivo. We discovered that a middle region rich in arginine residues (296SRRTGIRYSRIGNKQTLRTRS316) functions as a nuclear retention sequence (NRS), as mutagenesis of critical arginine residues within this NRS reduced the fraction of L2 in the nucleus despite the presence of both NLSs. Significantly, the infectivity of HPV16 pseudoviruses containing either RR297AA or RR297EE within the L2 NRS was strongly reduced both in HaCaT cells and in a murine challenge model. Experiments using Ratjadone A nuclear export inhibitor and mutation-localization analysis lead to the discovery of a leucine-rich nuclear export signal (462LPYFFSDVSL) mediating 16L2 nuclear export. These data indicate that HPV16 L2 nucleocytoplasmic traffic is dependent on multiple functional transport signals

Bcl11a Deficiency Leads to Hematopoietic Stem Cell Defects with an Aging-like Phenotype

SummaryB cell CLL/lymphoma 11A (BCL11A) is a transcription factor and regulator of hemoglobin switching that has emerged as a promising therapeutic target for sickle cell disease and thalassemia. In the hematopoietic system, BCL11A is required for B lymphopoiesis, yet its role in other hematopoietic cells, especially hematopoietic stem cells (HSCs) remains elusive. The extensive expression of BCL11A in hematopoiesis implicates context-dependent roles, highlighting the importance of fully characterizing its function as part of ongoing efforts for stem cell therapy and regenerative medicine. Here, we demonstrate that BCL11A is indispensable for normal HSC function. Bcl11a deficiency results in HSC defects, typically observed in the aging hematopoietic system. We find that downregulation of cyclin-dependent kinase 6 (Cdk6), and the ensuing cell-cycle delay, correlate with HSC dysfunction. Our studies define a mechanism for BCL11A in regulation of HSC function and have important implications for the design of therapeutic approaches to targeting BCL11A

Differential expression of membrane metallo-endopeptidase, MME, in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding membrane metallo-endopeptidase, MME, when comparing primary tumors of the breast to the tissue of origin, the normal breast. MME was also differentially expressed in the tumor cells of patients with triple negative breast cancer. MME mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of MME in primary tumors of the breast was correlated with distant metastasis-free survival in patients with HER2+ cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. MME may be of relevance to initiation, maintenance or progression of cancers of the female breast

Differential expression of RERG-like, RERGL, in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding RERG-like, RERGL, when comparing primary tumors of the breast to the tissue of origin, the normal breast. RERGL was also differentially expressed in the tumor cells of patients with triple negative breast cancer. RERGL mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of RERGL in primary tumors of the breast was correlated with overall survival in patients with basal, luminal A, and luminal B subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. RERGL may be of relevance to initiation, maintenance or progression of cancers of the female breast

Differential expression of proteolipid protein 1 in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding proteolipid protein 1, PLP1, when comparing primary tumors of the breast to the tissue of origin, the normal breast. PLP1 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of PLP1 in primary tumors of the breast was correlated with overall survival in patients with luminal A cancers, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. PLP1 may be of relevance to initiation, maintenance or progression of cancers of the female breast

ANKRD50 is differentially expressed in the lymph node metastases of patients with breast cancer.

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that ankyrin repeat domain 50, ANKRD50, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. Analysis of a separate microarray dataset revealed that ANKRD50 was also differentially expressed in brain metastatic tissues (5). ANKRD50 mRNA was present at decreased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of ANKRD50 in primary tumors of the breast was correlated with patient overall survival, in lymph node positive patients but not in lymph node negative patients

GOSR1 is differentially expressed in lymph node metastasis in human breast cancer.

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that golgi SNAP receptor complex member 1, GOSR1, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. GOSR1 mRNA was present at decreased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of GOSR1 in primary tumors of the breast was correlated with patient overall survival, in lymph node positive patients but not in lymph node negative patients. Modulation of GOSR1 expression may be relevant to the biology by which tumor cells metastasize from the breast to the lymph nodes and the brain in humans with metastatic breast cancer

MXRA8 is differentially expressed in lymph node metastasis in human breast cancer.

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that matrix remodeling associated 8, MXRA8, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. MXRA8 mRNA was present at decreased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of MXRA8 in primary tumors of the breast was correlated with patient post-progression survival, in lymph node positive patients but not in lymph node negative patients. Modulation of MXRA8 expression may be relevant to the biology by which tumor cells metastasize from the breast to the lymph nodes and the brain in humans with metastatic breast cancer

The StAR-related lipid transfer protein STARD8 is differentially expressed in non-small cell lung adenocarcinomas.

Non-small cell lung adenocarcinoma (NSCLC) is the leading cause of cancer death in the United States (1, 2). We mined published microarray data (3, 4) to discover genes associated with NSCLC tumors. We identified significant differential expression of the StAR-related lipid transfer protein STARD8 in primary tumors from patients with NSCLC. STARD8 may be of relevance to the initiation, progression or maintenance of non-small cell lung cancers

PRKCB is differentially expressed in lymph node metastasis in human breast cancer.

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). Between the breast and the brain reside the secondary lymphoid organ, the lymph nodes. We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes for the discovery of genes associated with metastasis to the lymph nodes in humans with metastatic breast cancer. We found that protein kinase C beta, PRKCB, was among the genes whose expression was most different in the lymph node metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. PRKCB mRNA was present at increased quantities in lymph node metastases as compared to primary tumors of the breast. Importantly, expression of PRKCB in primary tumors of the breast was correlated with patient overall survival, in lymph node positive patients but not in lymph node negative patients. Modulation of PRKCB expression may be relevant to the biology by which tumor cells metastasize from the breast to the lymph nodes and the brain in humans with metastatic breast cancer