Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCFFBX4-αB Crystallin Complex

Douglas I. Lin; Olena Barbash; K. G.Suresh Kumar; Jason D. Weber; J. Wade Harper; Andres J J.P. Klein-Szanto; Anil Rustgi; Serge Y Y. Fuchs; J. Alan Diehl

doi:10.1016/j.molcel.2006.09.007

Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCF^{FBX4-αB Crystallin} Complex

Douglas I. Lin, Olena Barbash, K. G.Suresh Kumar, Jason D. Weber, J. Wade Harper, Andres J J.P. Klein-Szanto, Anil Rustgi, Serge Y Y. Fuchs, J. Alan Diehl

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321 Scopus citations

Abstract

Growth factor-dependent accumulation of the cyclin D1 proto-oncogene is balanced by its rapid phosphorylation-dependent proteolysis. Degradation is triggered by threonine 286 phosphorylation, which promotes its ubiquitination by an unknown E3 ligase. We demonstrate that Thr286-phosphorylated cyclin D1 is recognized by a Skp1-Cul1-F box (SCF) ubiquitin ligase where FBX4 and αB crystallin govern substrate specificity. Overexpression of FBX4 and αB crystallin triggered cyclin D1 ubiquitination and increased cyclin D1 turnover. Impairment of SCF^{FBX4-αB crystallin} function attenuated cyclin D1 ubiquitination, promoting cyclin D1 overexpression and accelerated cell-cycle progression. Purified SCF^{FBX4-αB crystallin} catalyzed polyubiquitination of cyclin D1 in vitro. Consistent with a putative role for a cyclin D1 E3 ligase in tumorigenesis, FBX4 and αB crystallin expression was reduced in tumor-derived cell lines and a subset of primary human cancers that overexpress cyclin D1. We conclude that SCF^{FBX4-αB crystallin} is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1.

Original language	English
Pages (from-to)	355-366
Number of pages	12
Journal	Molecular cell
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2006.09.007
State	Published - Nov 3 2006

Keywords

CELLCYCLE
PROTEINS

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10.1016/j.molcel.2006.09.007

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@article{b1f673830f124734a7042e87a9e12be1,

title = "Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCFFBX4-αB Crystallin Complex",

abstract = "Growth factor-dependent accumulation of the cyclin D1 proto-oncogene is balanced by its rapid phosphorylation-dependent proteolysis. Degradation is triggered by threonine 286 phosphorylation, which promotes its ubiquitination by an unknown E3 ligase. We demonstrate that Thr286-phosphorylated cyclin D1 is recognized by a Skp1-Cul1-F box (SCF) ubiquitin ligase where FBX4 and αB crystallin govern substrate specificity. Overexpression of FBX4 and αB crystallin triggered cyclin D1 ubiquitination and increased cyclin D1 turnover. Impairment of SCFFBX4-αB crystallin function attenuated cyclin D1 ubiquitination, promoting cyclin D1 overexpression and accelerated cell-cycle progression. Purified SCFFBX4-αB crystallin catalyzed polyubiquitination of cyclin D1 in vitro. Consistent with a putative role for a cyclin D1 E3 ligase in tumorigenesis, FBX4 and αB crystallin expression was reduced in tumor-derived cell lines and a subset of primary human cancers that overexpress cyclin D1. We conclude that SCFFBX4-αB crystallin is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1.",

keywords = "CELLCYCLE, PROTEINS",

author = "Lin, {Douglas I.} and Olena Barbash and Kumar, {K. G.Suresh} and Weber, {Jason D.} and Harper, {J. Wade} and Klein-Szanto, {Andres J J.P.} and Anil Rustgi and Fuchs, {Serge Y Y.} and Diehl, {J. Alan}",

note = "Funding Information: We thank M. Pagano for the FBX4, FBW2, CUL1, and SKP1 constructs, P. Sicinski for immortalized D1 −/− fibroblasts, S. Elledge for Fbx4 shRNA vectors, and M. Lessie for technical assistance. We thank members of the Diehl, Fuchs, Bassing, and Kushner labs for critical insight. This work was supported by grants from the NIH (CA93237 and CA111360), a Leukemia & Lymphoma Scholar award (J.A.D.), P01-CA098101 (A.R.), and the Abramson Cancer Center (J.A.D. and S.Y.F.). ",

year = "2006",

month = nov,

day = "3",

doi = "10.1016/j.molcel.2006.09.007",

language = "English",

volume = "24",

pages = "355--366",

journal = "Molecular cell",

issn = "1097-2765",

number = "3",

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TY - JOUR

T1 - Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCFFBX4-αB Crystallin Complex

AU - Lin, Douglas I.

AU - Barbash, Olena

AU - Kumar, K. G.Suresh

AU - Weber, Jason D.

AU - Harper, J. Wade

AU - Klein-Szanto, Andres J J.P.

AU - Rustgi, Anil

AU - Fuchs, Serge Y Y.

AU - Diehl, J. Alan

N1 - Funding Information: We thank M. Pagano for the FBX4, FBW2, CUL1, and SKP1 constructs, P. Sicinski for immortalized D1 −/− fibroblasts, S. Elledge for Fbx4 shRNA vectors, and M. Lessie for technical assistance. We thank members of the Diehl, Fuchs, Bassing, and Kushner labs for critical insight. This work was supported by grants from the NIH (CA93237 and CA111360), a Leukemia & Lymphoma Scholar award (J.A.D.), P01-CA098101 (A.R.), and the Abramson Cancer Center (J.A.D. and S.Y.F.).

PY - 2006/11/3

Y1 - 2006/11/3

N2 - Growth factor-dependent accumulation of the cyclin D1 proto-oncogene is balanced by its rapid phosphorylation-dependent proteolysis. Degradation is triggered by threonine 286 phosphorylation, which promotes its ubiquitination by an unknown E3 ligase. We demonstrate that Thr286-phosphorylated cyclin D1 is recognized by a Skp1-Cul1-F box (SCF) ubiquitin ligase where FBX4 and αB crystallin govern substrate specificity. Overexpression of FBX4 and αB crystallin triggered cyclin D1 ubiquitination and increased cyclin D1 turnover. Impairment of SCFFBX4-αB crystallin function attenuated cyclin D1 ubiquitination, promoting cyclin D1 overexpression and accelerated cell-cycle progression. Purified SCFFBX4-αB crystallin catalyzed polyubiquitination of cyclin D1 in vitro. Consistent with a putative role for a cyclin D1 E3 ligase in tumorigenesis, FBX4 and αB crystallin expression was reduced in tumor-derived cell lines and a subset of primary human cancers that overexpress cyclin D1. We conclude that SCFFBX4-αB crystallin is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1.

AB - Growth factor-dependent accumulation of the cyclin D1 proto-oncogene is balanced by its rapid phosphorylation-dependent proteolysis. Degradation is triggered by threonine 286 phosphorylation, which promotes its ubiquitination by an unknown E3 ligase. We demonstrate that Thr286-phosphorylated cyclin D1 is recognized by a Skp1-Cul1-F box (SCF) ubiquitin ligase where FBX4 and αB crystallin govern substrate specificity. Overexpression of FBX4 and αB crystallin triggered cyclin D1 ubiquitination and increased cyclin D1 turnover. Impairment of SCFFBX4-αB crystallin function attenuated cyclin D1 ubiquitination, promoting cyclin D1 overexpression and accelerated cell-cycle progression. Purified SCFFBX4-αB crystallin catalyzed polyubiquitination of cyclin D1 in vitro. Consistent with a putative role for a cyclin D1 E3 ligase in tumorigenesis, FBX4 and αB crystallin expression was reduced in tumor-derived cell lines and a subset of primary human cancers that overexpress cyclin D1. We conclude that SCFFBX4-αB crystallin is an E3 ubiquitin ligase that promotes ubiquitin-dependent degradation of Thr286-phosphorylated cyclin D1.

KW - CELLCYCLE

KW - PROTEINS

UR - http://www.scopus.com/inward/record.url?scp=33750460897&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2006.09.007

DO - 10.1016/j.molcel.2006.09.007

M3 - Article

C2 - 17081987

AN - SCOPUS:33750460897

SN - 1097-2765

VL - 24

SP - 355

EP - 366

JO - Molecular cell

JF - Molecular cell

IS - 3

ER -

Phosphorylation-Dependent Ubiquitination of Cyclin D1 by the SCF^{FBX4-αB Crystallin} Complex

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