Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway.
The four-and-a-half LIM (FHL) proteins belong to a family of LIM-only proteins that regulate cell proliferation, differentiation, and apoptosis. The exact functions of each FHL protein in cancer development and progression remain unknown. Here we report that FHL1, FHL2, and FHL3 physically and functionally interact with Smad2, Smad3, and Smad4, important regulators of cancer development and progression, in a TGF-beta-independent manner. Casein kinase 1delta, but not the TGF-beta receptor, was required for the FHL-mediated TGF-beta-like responses, including increased phosphorylation of Smad2/3, interaction of Smad2/3 and Smad4, nuclear accumulation of Smad proteins, activation of the tumor suppressor gene p21, and repression of the oncogene c-myc. FHL1-3 inhibited anchorage-dependent and -independent growth of a human hepatoma cell line in vitro and tumor formation in nude mice. Further analysis of clinical samples revealed that FHL proteins are often downregulated in hepatocellular carcinomas and that this correlates with decreased TGF-beta-like responses. By establishing a link between FHL proteins and Smad proteins, this study identifies what we believe to be a novel TGF-beta-like signaling pathway and indicates that FHL proteins may be useful molecular targets for cancer therapy.
Ding
Lihua
L
Beijing Institute of Biotechnology, Beijing, People's Republic of China.
Wang
Zhaoyun
Z
Yan
Jinghua
J
Yang
Xiao
X
Liu
Aijun
A
Qiu
Weiyi
W
Zhu
Jianhua
J
Han
Juqiang
J
Zhang
Hao
H
Lin
Jing
J
Cheng
Long
L
Qin
Xi
X
Niu
Chang
C
Yuan
Bin
B
Wang
Xiaohui
X
Zhu
Cui
C
Zhou
Yan
Y
Li
Jiezhi
J
Song
Haifeng
H
Huang
Cuifen
C
Ye
Qinong
Q
D000818:Animals; D048148:Casein Kinase Idelta / Q000502:physiology; D018398:Homeodomain Proteins / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D008114:Liver Neoplasms, Experimental / Q000517:prevention & control*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009124:Muscle Proteins / Q000502:physiology*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000502:physiology*
C101149:FHL1 protein, human; C105987:FHL2 protein, human; C117563:FHL3 protein, human; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D048148:Casein Kinase Idelta