scholarly journals Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2

Cell Reports ◽  
2019 ◽  
Vol 27 (10) ◽  
pp. 2859-2870.e6 ◽  
Author(s):  
Philipp Trulley ◽  
Goda Snieckute ◽  
Dorte Bekker-Jensen ◽  
Manoj B. Menon ◽  
Robert Freund ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Translation Initiation ◽  
Alternative Translation Initiation ◽  
Alternative Translation

Two Rat Surfactant Protein A Isoforms Arise by a Novel Mechanism That Includes Alternative Translation Initiation†

Biochemistry ◽  
2000 ◽  
Vol 39 (33) ◽  
pp. 10189-10195 ◽  
Author(s):  
Mamatha Damodarasamy ◽  
Mei Zhang ◽  
Krista Dienger ◽  
Francis X. McCormack
Keyword(s):  
Translation Initiation ◽  
Protein A ◽  
Surfactant Protein ◽  
Surfactant Protein A ◽  
Alternative Translation Initiation ◽  
Alternative Translation

Altered Kinetics and Localization of MMSET Variants Suggests That RE-IIBP Overexpression Is a Unifying Event in t(4;14)(p16;q32) Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 75-75 ◽  
Author(s):  
Jonathan J. Keats ◽  
Christopher A. Maxwell ◽  
Tony Reiman ◽  
Brian J. Taylor ◽  
Michael J. Mant ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Translation Initiation ◽  
Plasma Cells ◽  
Initiation Site ◽  
Protein Product ◽  
Full Length ◽  
Translation Initiation Site ◽  
Type I ◽  
Alternative Translation Initiation ◽  
Alternative Translation

Abstract Translocations involving the IgH locus are common genetic events in multiple myeloma (MM). A number of recurrent IgH translocations exist with t(11;14)(q13;q32) and t(4;14)(p16;q32) being the most common. These translocations predict for differential clinical outcomes, good versus poor, respectively. We have shown that ~70% of t(4;14) POS patients express the initially proposed target gene FGFR3. However, the t(4;14)POS/FGFR3NEG group of patients still fare poorly (P=0.01). Therefore, either the transformation event associated with t(4;14) is multifactorial or independent of FGFR3. The loss of FGFR3 expression is associated with the loss of der(14). However, der(4) is detectable in all t(4;14)POS patients at diagnosis and relapse, suggesting that it is biologically and clinically relevant. The der(4) chromosome is thought to result in the overexpression of MMSET. The genomic breakpoints associated with t(4;14) occur in the 5′ end of the MMSET locus. In 70% of patients (MB4-1), the breakpoints maintain the full length open reading frame of MMSET. In the remaining 30% (MB4-2 & MB4-3), the breakpoints occur downstream of the proper translation initiation site. Two principle transcripts originate from the MMSET gene. The first transcript initiates in the beginning of the MMSET locus and, as a result of alternative splicing of exon 12, produces either MMSET I or MMSET II. The second transcript initiates upstream of exon 10 and uses an alternative translation initiation site to produces RE-IIBP. MMSET I and II transcripts, produced by each breakpoint variant, and the RE-IIBP transcript, produced in all patients irrespective of breakpoint type, were cloned. Transcripts were C-terminally tagged with GFP and transiently transfected into HeLa cells. Anti-GFP immunoblots showed that all transcripts produced a protein product, even the MB4-2 and MB4-3 variants that utilize alternative translation initiation sites in exon 4 and 6, respectively. The wildtype/MB4-1 MMSET I and II constructs localized to the nucleus and were excluded from nucleoli. MMSET II is almost exclusively associated with chromatin while MMSET I localized diffusely. RE-IIBP localized primarily in cytoplasmic foci and to nucleoli. Unlike the full length MMSET proteins, the MB4-2/MB4-3 constructs localized to the nucleus but also localized in nucleoli. To determine if the N-terminus regulates the nuclear localization pattern, we cloned the N-terminal portion of MMSET, which is lost in the MB4-2 transcripts. As this construct localized to the nucleus and was excluded from nucleoli, therefore a domain required for the proper localization of MMSET is lost in the MB4-2/MB4-3 variants. Kinetic analysis of MMSET variants localized to the nucleoplasm shows that the association of MMSET II with chromatin is very stable, t1/2 130 sec, while the type II MB4-2 and MB4-3 breakpoint variants have reduced kinetics, t1/2 19 and 12 sec, respectively, suggesting a decreased stability of association. The reduction in kinetics is also seen in the type I variants. We verified the overexpression of RE-IIBP by quantitative RT-PCR on a panel of purified plasma cells and unpurified BMMC. RE-IIBP was overexpressed in t(4;14)POS patients, P=0.0009 and P=0.00006, respectively, making it the only overexpressed protein without altered function in all t(4;14)POS patients irrespective of FGFR3 expression or breakpoint type. Therefore, RE-IIBP may be of central importance to the poor outcome of t(4;14)POS MM patients.

scholarly journals Competitive Translation Efficiency at the Picornavirus Type 1 Internal Ribosome Entry Site Facilitated by Viral cis and trans Factors

2006 ◽  
Vol 80 (7) ◽  
pp. 3310-3321 ◽  
Author(s):  
Elena Y. Dobrikova ◽  
Rachel N. Grisham ◽  
Constanze Kaiser ◽  
Jennifer Lin ◽  
Matthias Gromeier
Keyword(s):  
Translation Initiation ◽  
Host Cells ◽  
Initiation Factor ◽  
Viral Gene ◽  
Translation Efficiency ◽  
Entry Site ◽  
Independent Manner ◽  
Translation Machinery ◽  
Alternative Translation Initiation ◽  
Alternative Translation

ABSTRACT Enteroviruses (EVs) overcome their host cells by usurping the translation machinery to benefit viral gene expression. This is accomplished through alternative translation initiation in a cap-independent manner at the viral internal ribosomal entry site (IRES). We have investigated the role of cis- and trans-acting viral factors in EV IRES translation in living cells. We observed that considerable portions of the viral genome, including the 5′-proximal open reading frame and the 3′ untranslated region, contribute to stimulation of IRES-mediated translation. With the IRES in proper context, translation via internal initiation in uninfected cells is as efficient as at capped messages with short, unstructured 5′ untranslated regions. IRES function is enhanced in cells infected with the EV coxsackievirus B3, but the related poliovirus has no significant stimulatory activity. This differential is due to the inherent properties of their 2A protease and is not coupled to 2A-mediated proteolytic degradation of the eukaryotic initiation factor 4G. Our results suggest that the efficiency of alternative translation initiation at EV IRESs depends on a properly configured template rather than on targeted alterations of the host cell translation machinery.

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