HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 3, 1539-1543, January 19, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/3/1539    most recent C600198200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Izquierdo, J. M. Articles by Valcárcel, J. Search for Related Content PubMed PubMed Citation Articles by Izquierdo, J. M. Articles by Valcárcel, J. Social Bookmarking                      What's this?

Fas-activated Serine/Threonine Kinase (FAST K) Synergizes with TIA-1/TIAR Proteins to Regulate Fas Alternative Splicing^*

José M. Izquierdo¹ and Juan Valcárcel^¶||

From the Centro de Biología Molecular "Severo Ochoa"-Universidad Autónoma de Madrid (CBMSO-UAM), Cantoblanco 28049 Madrid, Spain and the Centre de Regulació Genòmica, ^¶Institució Catalana de Recerca i Estudis Avançats (ICREA), ^||Universitat Pompeu Fabra, Passeig Marítim, 37-49, 08003 Barcelona, Spain

The factors and mechanisms that mediate the effects of intracellular signaling cascades on alternative pre-mRNA splicing are poorly understood. TIA-1 (T-cell intracellular antigen 1) and TIAR (TIA-1-related) proteins regulate alternative pre-mRNA splicing by promoting the use of suboptimal 5' splice sites followed by uridine-rich intronic enhancer sequences. These proteins promote, for example, inclusion of Fas receptor exon 6, which leads to an mRNA encoding a pro-apoptotic form of the receptor at the expense of the form that skips exon 6, which encodes an anti-apoptotic form. Fas-activated serine/threonine kinase (FAST K) is known to interact with and phosphorylate TIA-1. Here we have tested the possibility that FAST K influences alternative pre-mRNA splicing by affecting the activity of TIA-1/TIAR. Depletion of FAST K form Jurkat cells leads to skipping of exon 6 from endogenous Fas transcripts. Conversely, FAST K overexpression enhances exon 6 inclusion of Fas reporters transfected in HeLa cells. Consistent with the possibility that the effects of FAST K are mediated by changes in the function of TIA-1/TIAR, the effects of FAST K overexpression (i) are largely suppressed by depletion of TIA-1 and TIAR and (ii) are significantly compromised by mutation of a TIA-1/TIAR-responsive enhancer present downstream of exon 6 5' splice site. Furthermore, in vitro phosphorylation of TIA-1 by FAST K results in enhanced U1 snRNP recruitment. Interestingly, this enhancement is not due to increased binding of TIA-1 to the pre-mRNA. Taken together, the results connect Fas signaling with the activity of splicing factors that modulate Fas alternative splicing, suggesting the existence of an autoregulatory loop that could serve to amplify Fas responses.

Received for publication, July 28, 2006 , and in revised form, November 10, 2006.

^* This work was supported by a grant from the Fondo de Investigaciones Sanitarias (PI051605) (to J. M. I.). The CBMSO received an institutional grant from Fundación Ramón Areces, Spain. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Centro de Biología Molecular "Severo Ochoa"-Universidad Autónoma de Madrid (CBMSO-UAM), Facultad de Ciencias, Módulo C-V, Lab. 230, Cantoblanco 28049, Madrid, Spain. Tel.: 34-914978461; Fax: 34-914974799; E-mail: jmizquierdo{at}cbm.uam.es.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. van Doorn, M. S. van Kester, R. Dijkman, M. H. Vermeer, A. A. Mulder, K. Szuhai, J. Knijnenburg, J. M. Boer, R. Willemze, and C. P. Tensen Oncogenomic analysis of mycosis fungoides reveals major differences with Sezary syndrome Blood, January 1, 2009; 113(1): 127 - 136. [Abstract] [Full Text] [PDF]

				K. Fushimi, P. Ray, A. Kar, L. Wang, L. C. Sutherland, and J. Y. Wu Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5 PNAS, October 14, 2008; 105(41): 15708 - 15713. [Abstract] [Full Text] [PDF]

				J. M. Izquierdo Fas Splicing Regulation during Early Apoptosis Is Linked to Caspase-mediated Cleavage of U2AF65 Mol. Biol. Cell, August 1, 2008; 19(8): 3299 - 3307. [Abstract] [Full Text] [PDF]

				J. M. Izquierdo Hu Antigen R (HuR) Functions as an Alternative Pre-mRNA Splicing Regulator of Fas Apoptosis-promoting Receptor on Exon Definition J. Biol. Chem., July 4, 2008; 283(27): 19077 - 19084. [Abstract] [Full Text] [PDF]

				S. Stamm Regulation of Alternative Splicing by Reversible Protein Phosphorylation J. Biol. Chem., January 18, 2008; 283(3): 1223 - 1227. [Abstract] [Full Text] [PDF]

				H. S. Kim, Y. Kuwano, M. Zhan, R. Pullmann Jr., K. Mazan-Mamczarz, H. Li, N. Kedersha, P. Anderson, M. C. J. Wilce, M. Gorospe, et al. Elucidation of a C-Rich Signature Motif in Target mRNAs of RNA-Binding Protein TIAR Mol. Cell. Biol., October 1, 2007; 27(19): 6806 - 6817. [Abstract] [Full Text] [PDF]

				J. M. Izquierdo and J. Valcarcel Two Isoforms of the T-cell Intracellular Antigen 1 (TIA-1) Splicing Factor Display Distinct Splicing Regulation Activities: CONTROL OF TIA-1 ISOFORM RATIO BY TIA-1-RELATED PROTEIN J. Biol. Chem., July 6, 2007; 282(27): 19410 - 19417. [Abstract] [Full Text] [PDF]

				M. Simarro, D. Mauger, K. Rhee, M. A. Pujana, N. L. Kedersha, S. Yamasaki, M. E. Cusick, M. Vidal, M. A. Garcia-Blanco, and P. Anderson Fas-activated serine/threonine phosphoprotein (FAST) is a regulator of alternative splicing PNAS, July 3, 2007; 104(27): 11370 - 11375. [Abstract] [Full Text] [PDF]