The atp6 Coding Region Has Been Disrupted and a Novel Reading Frame Generated in the Mitochondrial Genome of Cytoplasmic Male-sterile Radish"

The gene atp6, encoding subunit 6 of the mitochondrial Fo-ATPase complex, has been characterized from both the normal (fertile) and Ogura (male-sterile) radish cytoplasms in order to determine if previously identified atp6 transcriptional differences could play a role in cytoplasmic maIe sterility. Normal radish atp6 encodes a 262-amino acid polypeptide that exhibits approximately 80% sequence identity with other plant atp6 polypeptides. A tRNA""' gene is located 150 base pairs 5' to atp6, and the two genes may be co-transcribed. As a result of extensive rearrangement, sequences that comprise the normal atp6 locus are present in three widely separated regions of the Ogura mitochondrial genome. Both 5' and 3' rearrangement breakpoints have been identified and found to be associated with short repeated sequences. The normal and Ogura atp6 loci share a common 987-base pair region containing most of the atp6 coding region and 106 base pairs of the 3'-flanking region. A 105-codon open reading frame is transcribed as the first gene of an Ogura atp6 bicistroaic mRNA. This sequence is not present in normal radish mitochondrial DNA. There are many nucleotide differences in the Ogura atp6 5'-flanking and coding regions that can be expected to eliminate normal translation of atp6. At least two possibilities exist for translation of Ogura atp6, both of which would result in an NHz-terminal amino acid sequence different from that of normal radish

Characterization of radish mitochondrial atpA: influence of nuclear background on transcription of atpA -associated sequences and relationship with male sterility

We have previously shown that the mitochondrial gene atpA , encoding the α subunit of F 1 ATP synthase, is associated with DNA rearrangements and nuclear-specific transcript patterns in the male-sterile cytoplasm of Ogura radish. Here we present a detailed characterization of this gene from both the normal (fertile) and Ogura (male-sterile) cytoplasms of radish to determine if it is involved in Ogura cytoplasmic male sterility. The normal and Ogura radish atpA loci are virtually identical for 3.8 kb, including a 507 codon open reading frame whose product is approximately 92% identical to other plant ATPA polypeptides. Rearrangement breakpoints have been identified 613 bp 5′ and 1663 bp 3′ to the atpA coding region. The 5′ rearrangement breakpoint is located within a repeated sequence that has been associated with other rearrangement events in radish mitochondria. The previously identified transcript difference results from transcription originating upstream of this rearrangement site. Although the presence of this transcript is affected by nuclear background, analyses in several different sterile and fertile nuclear backgrounds indicate that the presence of this transcript is not strictly correlated with male sterility. In addition, normal levels of ATPA polypeptide are present in sterile plants containing the Ogura cytoplasm.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43427/1/11103_2004_Article_BF00016123.pd

Cleavage of NIK by the API2-MALT1 Fusion Oncoprotein Leads to Noncanonical NF-kappa B Activation

Proper regulation of nuclear factor kappa B (NF-kappa B) transcriptional activity is required for normal lymphocyte function, and deregulated NF-kappa B signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-kappa B-inducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-kappa B signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-kappa B pathway in B lymphoproliferative disease.status: publishe

Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma

Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of “MCC signature” genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV− MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC