E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors

Abstract

Steroid hormone receptors (SHR) belong to a large family of ligand-activated transcription factors that perform their biological functions by enhancing the transcription of specific target genes. The transactivation functions of SHRs are regulated by a specialized group of proteins called coactivators. The SHR coactivators represent a growing class of proteins with various enzymatic activities that serve to modify the chromatin to facilitate the transcription of SHR target genes. The ubiquitin-proteasome pathway enzymes have also been added to the growing list of enzymatic activities that are recruited to the SHR target gene promoters during transcription. One such ubiquitin-proteasome pathway enzyme to be identified and characterized as a SHR coactivator was E6-associated protein (E6-AP). E6-AP is a hect (homologous to E6-associated protein carboxy-terminal domain) domain containing E3 ubiquitin ligase that possesses two independent separable functions; a coactivation function and an ubiquitin-protein ligase activity. Being a component of the ubiquitin-proteasome pathway, it is postulated that E6-AP may orchestrate the dynamics of steroid hormone receptor-mediated transcription by regulating the degradation of the transcriptional complexes. E6-AP has also been shown to be involved in the regulation of various aspects of reproduction such as prostate and mammary gland development. Furthermore, it has been demonstrated that E6-AP expression is down-regulated in breast and prostate tumors and that the expression of E6-AP is inversely associated with that of estrogen and androgen receptors. This review summarizes our current knowledge about the structures, molecular mechanisms, spatiotemporal expression patterns and biological functions of E6-AP.

References

Alarid

E. T.

(2006). Lives and times of nuclear receptors Mol Endocrinol 20, 1972–81.

Cooper

, Schneider

, Bohl

, Jiang

, Beaudet

, and Vande Pol

(2003). Requirement of E6AP and the features of human papillomavirus E6 necessary to support degradation of p53 Virology 306, 87–99.

Dhananjayan

S. C.

, Ramamoorthy

, Khan

O.Y.

, Ismail

, Sun

, Slingerland

, O'Malley

B. W.

, and Nawaz

(2006). WW domain binding protein-2, an E6-associated protein interacting protein, acts as a coactivator of estrogen and progesterone receptors Mol Endocrinol 20, 2343–54.

Dindot

S. V.

, Antalffy

B. A.

, Bhattacharjee

M. B.

, and Beaudet

A. L.

(2008). The Angelman syndrome ubiquitin ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic spine morphology Hum Mol Genet 17, 111–8.

Dornan

, Wertz

, Shimizu

, Arnott

, Frantz

G. D.

, Dowd

, O'Rourke

, Koeppen

, and Dixit

V. M.

(2004). The ubiquitin ligase COP1 is a critical negative regulator of p53 Nature 429, 86–92.

Fang

, Lev-Lehman

, Tsai

T. F.

, Matsuura

, Benton

C. S.

, Sutcliffe

J. S.

, Christian

S. L.

, Kubota

, Halley

D. J.

, Meijers-Heijboer

, Langlois

, Graham

J. M.

Jr. , Beuten

, Willems

P. J.

, Ledbetter

D. H.

, and Beaudet

A. L.

(1999). The spectrum of mutations in UBE3A causing Angelman syndrome Hum Mol Genet 8, 129–35.

Gao

, Mohsin

S. K.

, Gatalica

, Fu

, Sharma

, and Nawaz

(2005). Decreased expression of e6-associated protein in breast and prostate carcinomas Endocrinology 146, 1707–12.

Gao

, Loggie

B. W.

, and Nawaz

(2002). The roles of sex steroid receptor coregulators in cancer Mol Cancer 1, 7.

Huang

, Kinnucan

, Wang

, Beaudenon

, Howley

P. M.

, Huibregtse

J. M.

, and Pavletich

N. P.

(1999). Structure of an E6AP-UbcH7 complex: insights into ubiquitination by the E2–E3 enzyme cascade Science 286, 1321–6.

10.

Huibregtse

J. M.

, Scheffner

, Beaudenon

, and Howley

P. M.

(1995). A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase Proc Natl Acad Sci U S A 92, 2563–7.

11.

Huibregtse

J. M.

, Scheffner

, and Howley

P. M.

(1993). Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins Mol Cell Biol 13, 4918–27.

12.

Ismail

, and Nawaz

(2005). Nuclear hormone receptor degradation and gene transcription: an update IUBMB Life 57, 483–90.

13.

James

M. A.

, Lee

J. H.

, and Klingelhutz

A. J.

(2006). HPV16-E6 associated hTERT promoter acetylation is E6AP dependent, increased in later passage cells and enhanced by loss of p300 Int J Cancer 119, 1878–85.

14.

Jiang

Y. H.

, Armstrong

, Albrecht

, Atkins

C. M.

, Noebels

J. L.

, Eichele

, Sweatt

J. D.

, and Beaudet

A. L.

(1998). Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation Neuron 21, 799–811.

15.

Kao

W. H.

, Beaudenon

S. L.

, Talis

A. L.

, Huibregtse

J. M.

, and Howley

P. M.

(2000). Human papillomavirus type 16 E6 induces self-ubiquitination of the E6AP ubiquitin-protein ligase J Virol 74, 6408–17.

16.

Khan

O. Y.

, Fu

, Ismail

, Srinivasan

, Cao

, Tu

, Lu

, and Nawaz

(2006). Multifunction steroid receptor coactivator, E6-associated protein, is involved in development of the prostate gland Mol Endocrinol 20, 544–59.

17.

Kishino

, and Wagstaff

(1998). Genomic organization of the UBE3A/E6-AP gene and related pseudogenes Genomics 47, 101–7.

18.

Kishino

, Lalande

, and Wagstaff

(1997). UBE3A/E6-AP mutations cause Angelman syndrome Nat Genet 15, 70–3.

19.

Kumar

, Talis

A. L.

, and Howley

P. M.

(1999). Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination J Biol Chem 274, 18785–92.

20.

Kumar

, Kao

W. H.

, and Howley

P. M.

(1997). Physical interaction between specific E2 and Hect E3 enzymes determines functional cooperativity J Biol Chem 272, 13548–54.

21.

Leng

R. P.

, Lin

, Ma

, Wu

, Lemmers

, Chung

, Parant

J. M.

, Lozano

, Hakem

, and Benchimol

(2003). Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation Cell 112, 779–91.

22.

, Brooks

C. L.

, Wu-Baer

, Chen

, Baer

, and Gu

(2003). Mono- versus polyubiquitination: differential control of p53 fate by Mdm2 Science 302, 1972–5.

23.

Liu

, Disbrow

G. L.

, Yuan

, Tomaic

, and Schlegel

(2007). Myc and human papillomavirus type 16 E7 genes cooperate to immortalize human keratinocytes J Virol 81, 12689–95.

24.

Liu

, Yuan

, Fu

, Disbrow

G. L.

, Apolinario

, Tomaic

, Kelley

M. L.

, Baker

C. C.

, Huibregtse

, and Schlegel

(2005). The E6AP ubiquitin ligase is required for transactivation of the hTERT promoter by the human papillomavirus E6 oncoprotein J Biol Chem 280, 10807–16.

25.

Lonard

D. M.

, Nawaz

, Smith

C. L.

, and O'Malley

B. W.

(2000). The 26S proteasome is required for estrogen receptor-α and coactivator turnover and for efficient estrogen receptor-α transactivation Mol Cell 5, 939–48.

26.

Mani

, Oh

A. S.

, Bowden

E.T.

, Lahusen

, Lorick

K. L.

, Weissman

A. M.

, Schlegel

, Wellstein

, and Riegel

A.T.

(2006). E6AP mediates regulated proteasomal degradation of the nuclear receptor coactivator amplified in breast cancer 1 in immortalized cells Cancer Res 66, 8680–6.

27.

Nawaz

, Lonard

D. M.

, Dennis

A. P.

, Smith

C. L.

, and O'Malley

B. W.

(1999b). Proteasome-dependent degradation of the human estrogen receptor Proc Natl Acad Sci U S A 96, 1858–62.

28.

Nawaz

, Lonard

D. M.

, Smith

C. L.

, Lev-Lehman

, Tsai

S.Y.

, Tsai

M. J.

, and O'Malley

B. W.

(1999a). The Angelman syndrome-associated protein, E6-AP, is a coactivator for the nuclear hormone receptor superfamily Mol Cell Biol 19, 1182–9.

29.

Nawaz

, and O'Malley

B. W.

(2004). Urban renewal in the nucleus: is protein turnover by proteasomes absolutely required for nuclear receptor-regulated transcription? Mol Endocrinol 18, 493–9.

30.

Nicholls

R. D.

, and Knepper

J. L.

(2001). Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes Annu Rev Genomics Hum Genet 2, 153–75.

31.

Nuber

, Schwarz

S. E.

, and Scheffner

(1998). The ubiquitin-protein ligase E6-associated protein (E6-AP) serves as its own substrate Eur J Biochem 254, 643–9.

32.

Oda

, Kumar

, and Howley

P. M.

(1999). Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination Proc Natl Acad Sci U S A 96, 9557–62.

33.

Peters

S. U.

, Goddard-Finegold

, Beaudet

A. L.

, Madduri

, Turcich

, and Bacino

C. A.

(2004). Cognitive and adaptive behavior profiles of children with Angelman syndrome Am J Med Genet A 128, 110–3.

34.

Pickart

C. M.

(2001). Mechanisms underlying ubiquitination Annu Rev Biochem 70, 503–33.

35.

Reid

, Hubner

M. R.

, Metivier

, Brand

, Denger

, Manu

, Beaudouin

, Ellenberg

, and Gannon

(2003). Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling Mol Cell 11, 695–707.

36.

Rochette-Egly

(2005). Dynamic combinatorial networks in nuclear receptor-mediated transcription J Biol Chem 280, 32565–8.

37.

Salvat

, Wang

, Dastur

, Lyon

, and Huibregtse

J. M.

(2004). The -4 phenylalanine is required for substrate ubiquitination catalyzed by HECT ubiquitin ligases J Biol Chem 279, 18935–43.

38.

Scheffner

, Huibregtse

J. M.

, and Howley

P. M.

(1994). Identification of a human ubiquitin-conjugating enzyme that mediates the E6-AP-dependent ubiquitination of p53 Proc Natl Acad Sci U S A 91, 8797–801.

39.

Scheffner

, Nuber

, and Huibregtse

J. M.

(1995). Protein ubiquitination involving an E1-E2–E3 enzyme ubiquitin thioester cascade Nature 373, 81–3.

40.

Scheffner

, Huibregtse

J. M.

, Vierstra

R. D.

, and Howley

P. M.

(1993). The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53 Cell 75, 495–505.

41.

Smith

C. L.

, DeVera

D. G.

, Lamb

D. J.

, Nawaz

, Jiang

Y. H.

, Beaudet

A. L.

, and O'Malley

B. W.

(2002). Genetic ablation of the steroid receptor coactivator-ubiquitin ligase, E6-AP, results in tissue-selective steroid hormone resistance and defects in reproduction Mol Cell Biol 22, 525–35.

42.

Sutcliffe

J. S.

, Jiang

Y. H.

, Galijaard

R. J.

, Matsuura

, Fang

, Kubota

, Christian

S. L.

, Bressler

, Cattanach

, Ledbetter

D. H.

, and Beaudet

A. L.

(1997). The E6-Ap ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region Genome Res 7, 368–77.

43.

Talis

A. L.

, Huibregtse

J. M.

, and Howley

P. M.

(1998). The role of E6AP in the regulation of p53 protein levels in human papillomavirus (HPV)-positive and HPV-negative cells J Biol Chem 273, 6439–45.

44.

Vaeteewoottacharn

, Chamutpong

, Ponglikitmongkol

, and Angeletti

P. C.

(2005). Differential localization of HPV16 E6 splice products with E6-associated protein Virol J 2, 50.

45.

Yamamoto

, Huibregtse

J. M.

, and Howley

P. M.

(1997). The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing Genomics 41, 263–6.

46.

Zanier

, Charbonnier

, Baltzinger

, Nomine

, Altschuh

, and Trave

(2005). Kinetic analysis of the interactions of human papillomavirus E6 oncoproteins with the ubiquitin ligase E6AP using surface plasmon resonance J Mol Biol 349, 401–12.