Signal trankduction: Lawrence

D. Kerr, Jun-ichiro The Salk Institute,

the nuclear


lnoue and lnder M. Verma

San Diego,



Fos and jun heterodimers activate the transcription of genes containing an AP-1 site. The activity of Fos and Jun proteins is regulated by post-translational modification. The activity of the rellNF-xB family of transcriptional factors is regulated by their sequestration in the cytoplasm in association with the inhibitor protein, IxB. An ankyrin repeat motif in IxB proteins is required for their direct association with rel/NF-xB. Current


in Cell Biology 1992, 4:49&501

Introduction The immediate response of the cell to a plethora of external signals is the ‘turning on’ of a set of genes, collectively referred to as immediate early genes. Induction of these genes is rapid and usually occurs in the absence of protein synthesis, suggesting the existence of sophisticated pathways that await activation to initiate the cascade of events leading to gene expression. Thus, the first stage of the cellular response culminates in the expression of transactivating proteins that then influence the transcription of a host of downstream genes involved in cell proliferation, differentiation and development. Thus, the nucleus is both the target of upstream signals and the transmitter of downstream tierent signals. An exquisite regulation of some of the early response genes is therefore essential for the wellbeing of the cell. It is not surprising that any aberrant regulation of the immediate early genes can cause uncontrolled cell growth invariably leading to neoplastic transformation. In this short review we will focus on two paradigms to illustrate the regulation of nuclear proto-oncogenes in the process of signal transduction.

The fos/jun The intracellular

conspiracy signals

Transcription of the fos and jzrn gene family members is transiently induced in many cell types by a wide variet) of external stimuli that include serum, growth factors, cytokines, neurotransmitters, phorbol esters, ultraviolet radiation, liver regeneration, ischemia, seizure and viral infection [ l*=,2**,3=]. These diverse agents elicit their effects through one or more of the following signal pathways: the protein tyrosine kinase system; the protein kinase C (PKC)-dependent activated pathway; a cAMPmediated cascade; a

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%I It’:\%; 1’. I..\\\.\K A. The ,\!)~>f1 Gene Family Nodal Point During Specification of the Muscle Cell Lineage. \‘irt,\ IM: Alteration of a cAMP-dependent protein Kinase Phosphoylation Site in c-fos Protein Augments its Transforming Potential. .1/o/ CV// Hw/ 1992. 12:99K- I CKlh.




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sion of the Fos-mediated

I.O\\‘.\~; (1. SI;l’lWK(; Il. >II’lJJK 1~. ~?I’~f~S-rrpr~SMoux c./os Promoter: a Novel Mechanism of Trrrrzs-regulation. c.ti// 19X9. 59:Wr)u Ii )O-

I’. DER CJ. VEK~~A IM: Ras-induced NeuronaI Differentiation of PC12 Cells: Possible Involvement of Fos and Jun. .Ifo/ Cell Rio/ 1989, 9:317t31X3.

Cltlt’ R. AXXI. I’. I\;..\HI\: \I, Jun.B Properties from, and is a Negative 19X9, 59:y’)&Wl

P. VIWAIY~R J, Lfl. MuoN PL. VEK,W\ IM: Induction of Proto-oncogene fos Transcription Through the Adenylate Cyclase Pathway: Characterization of a CAMPresponsive Element. &fre.s f&, 1988. 2: 152% 1538.

Jun-B Inhibits Trdns-activating






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Differs in its BiologicaI Regulator of. c.Jun. (.>I/

s, I+lw)HKo J. \Irsx;\ J: the Transforming and // 19X9. 59-9X7-99-,

F. Cl‘KJuL ‘I’. \fIIJ.l~K Al). \‘I-KXlA l%l. Removal of a 6?-base-pair Sequence in the Noncoding Region of Protooncogenes fos Converts it to a Transforming (;enc. 1%~. .Vrcl/ :licri/ .Sci I ‘Y.4 19X5, HZ+H~Wl. I\ll:III.Ixh


GIL%Q4 .MZ: The c-fos Serum Response Element Responds to Protein Kinase C-dependent and -independent Signals but not to Cyclic AMP. Gerles .I%[* 1988, 2:39+-+02.











G, GREENBERG ME: Calcium of c-Jos Transcriptional Ac-



SS. S&W)N~ COK~I I’: More is Better. Activators and from the Same Gene. Q// 1992. 68-1 I I--f I-I

Signal BOYLE SJ. SMFAI. T. DEFIX LHK, ANGIX I’, U’OOIXX-IT JR, KARIN M. H~INI‘EH T. Activation of Protein Kinase C Decreases Phosphorylation of c-Jun at Sites that Negatively Regulate its DNA-binding Activity. Cell 1991. 64:573-5%. This manuscript describes how phosphwylation of jun protein by PKC decreases i& DNA-binding activiv. 29. .


A~~Rx J. SASSONKOILSI fos/jun Whose Activity Cdl 1991, 64:9x3-993.


GIIMOHI; T: NF-xB, 1990. 62:H‘i I -x-l3.

P IP-I: a Dominant Inhibitor is Modulated by Phosphorylation.









NOIAN GP. BNII’IM~KI; I): The Inhibitory nn&~~Yn and Activator Rel Proteins. C!drr O/~nr C;c~c,( O~‘I: 1992. 2.71 I-220. this rcyem review e.uamines rhc NF-x13. rcl and dorsal proteins and their spc4ic inhihitors in the conrrol of both normal and aherrdnt gmc cxprcssion.

PA: The Inducible Transcription Regulation by Distinct Protein Subunits. Ackr 1991, 1072:63-X0. This derailed rc\icw cc)mprehensi\~vly and spccitically chemical pnq~cnies of horh NF xl3 and Ix13 pnGn5.

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Activator HioclUnr

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S(:I~XII’I% MI.. I II;NKI:I. ‘I‘. I~AI:I~IXIJ~ PA. Proteins the Nuclear Uptake of NF-xB. Rel and Dorsal. Niol 1991. 1.13- 1.3’.

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El’. Ptwli~ NJ, I IA~IIN~: M. GKl;li~li WC. The v- fd Oncogene Encodes a xB Enhancer Binding Protein that Inhibits NF-xB Function. Cc,// I~990)().63:X03 -HI -I The authors Idcnd& rhr xl3 cnhanccr hinclmg ~.ornIx )nems on Ihc Il.-L receptor a-promow a.5 relatc~l 10 rhc v-4 prolrin sncl the inhihltoq action of v rel protein on promoters beuing XI3 siw. .


Irwiw J-I. KIW 1.1). RANK)NE I,1. I~I~;\;c;,u. E. Iwms or. W:tw IM C-rel Activates hut v-rel Suppresses Transcription from xB Sites. /‘UK- ,Vtr// .*lctrt/ Sit I ‘Sd 1991, BB:3’15-3’19. This manu5crip~ cl0crihc.s thal kvhile horh v 2nd L’rel hind IO xl3 silt \ry &kGMly. only c rel can c‘;ww IransacIiwtlon of genes conraining the xl3 hiw hlore m~lxmantl~~. v rcI mhihits acW;mon of genes link4 10 xl3 silt presum:~l~ly hy acring :c1 3 tran~d~~mm3m1 nepativc muI;Im. 36. .



V, K~I:IUI.S~ I’. I~~LwI. A, NF-xB and Related Proteins: Rel/dorsaI Homologies iMeet Ankyrin-like Repeats. ~‘ww/.s fkdKvn si/ 1992, 17: 135- 110.


FAN C M. ~~ANIATIS T. Generation Processing of ~105 Through .wrrrrw I99 I, 351~3v5-39x.

of p50 Subunit of NF-xB h! an ATP-dependent Pathway.



the nuclear


Kerr, Inoue,


J-I, KERR LD. KAKIZIIKA A, VERMA IM: IxBy, a 70kd Protein Identical to the C-terminal HaIf of ~110 NF-xB: a New Member of the IxB Family. Cell 1992. 68:1109-1120. INOLF

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K~R LD. INOLJE J-I. DAVIS N. LINK E, BAEUERLE PA, BOSE HR JR, VI:RMA IM: The Rel-associated pp40 Protein Prevents DNA Binding of Ret and NF-xB: Relationship with IxBfi and Reg ulation by Phosphorylation. Genes De)erp1991, 5:1464-1476. This manuscript describes how cellular proteins associated with v-or c-rel proteins can modulate their DNA-binding activity. Gliosii S. hl.llh4ORE D: Activation phorylation of its Inhibitor IxB.

in o&o of NF-xB by PhosScience 1990, 344:67tiBO.

I.11 D. THOMIJSON JD. GOltslil GK. Rlcr; NR, MA>‘ER MG. YlINIS JJ: Alterations at the rel Locus in Human Lymphoma. Onto gene 1991. 6:1235-12-il. DALI> N. BARGhIANN W. LIhl MY. BOSE HR JR: Avian ReticuIoendotheliosis Virus-transformed Lymphoid Cells Contain Multiple p~59’-‘~’ Complexes. J l’irol 1990. 64:583-591. OIINO H, T,U(IMOTO G, Mc~~EITI-IA~\~ TW: The Candidate Proto-oncogene &cl-3 is Related to Genes Implicated in Cell Lineage Determination and Cell Cycle Control. Cell 1990, 60:991-997. 1.1.x SE. JOIIN KM. BI:NNKTT \‘: Analysis of cDNA for Human Erythrocyte Anhyrin Indicates a Repeated Structure with Homology to Tissue-differentiation and Cell-cycle Control Proteins. NCIIIOP 1990. 344:36+2. IAMAH(:c) K. T~iowso:~ CC. BYI% BP, WALTON EM, MCKNICHT SL. Identification of Ets- and Notch-related Subunits in GA Binding Protein. Scimcc 1991. 253:78+792. INOIW J-I. KERR II>, RA~HII) I>. DAVIS N, BOSE HR JR, Vmhi~ IM: Direct Asociation of pp4O/IxBe with rel/NF-xB Transcription Factors: Role of Ankyrin Repeats in the Inhibition of DNA Binding Activity. I’roc ~Vrrfl flc& Sci l’S.4 1992, 89:-1333+33’. This manuscrilx dcacrilxb the role of ank~rin reptws in the function of IxH prowins. It shows thar there are direct associations of transcription facrors NIz-x13 rc’I nith 1x13 proteins.

ID Kerr. IX1 Verma. Molecular Riolo* 2nd Virolo~ SJlk Instirutc. P.O. 130x X5X(X). San Diego, California

l;ihontog. 92IH6~iXOO.

J-II Inouc-. Cancer Institurr. Department of Esperimental I .‘I’ I, Kaml-lkehukun,. Toshmra-ku. Tokyo 170. Japan.




Signal transduction: the nuclear target.

Fos and jun heterodimers activate the transcription of genes containing an AP-1 site. The activity of Fos and Jun proteins is regulated by post-transl...
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