Disease relevance of FHL2

• In the present study, we show that FOXO1 interacts with four and a half LIM 2 (FHL2) in prostate cancer cells [1].
• Thus, the interaction with HPV-16 E7 leads to a promoter-specific impairment of FHL2 function and this may contribute to cell transformation [2].
• Reverse transcription polymerase chain reaction analysis showed that FHL2 mRNA levels may be downregulated in many breast cancer cell lines [3].
• Besides, in Northern blot hybridization of human cancer cell lines, the highest FHL2 mRNA expression was detected in colorectal adenocarcinoma SW480 and HeLa cell S3 [4].
• Our immunohistochemistry data showed that FHL2 protein expression is also augmented in epithelial ovarian cancer [5].
• FHL2 expression was up-regulated in gastrointestinal cancer, compared with matched normal tissues [6].

High impact information on FHL2

• Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation [1].
• The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus [7].
• In addition, the transcription of the prostate-specific AR target gene probasin is coactivated by FHL2 [8].
• FHL2 contains a strong, autonomous transactivation function and binds specifically to the AR in vitro and in vivo [8].
• In an agonist- and AF-2-dependent manner FHL2 selectively increases the transcriptional activity of the AR, but not that of any other nuclear receptor [8].

Chemical compound and disease context of FHL2

• In the absence of FHL2, however, cardiac hypertrophy resulting from chronic infusion of isoproterenol is exaggerated (59% versus 20% increase in heart weight/body weight in FHL null versus wild-type mice; P<0.01) [9].

Biological context of FHL2

• Furthermore, we found that FHL2 significantly increased acetylation of beta-catenin by p300 in vivo [10].
• The minimal binding sites for FHL2 and FHL3 on beta(1A)-chain overlap, whereas on alpha(7A) and alpha(7B) subunits they are situated adjacent [11].
• Protein-protein interaction of FHL3 with FHL2 and visualization of their interaction by green fluorescent proteins (GFP) two-fusion fluorescence resonance energy transfer (FRET) [12].
• However, overexpression of full-length FHL2 did not affect ERalpha-dependent transcriptional activities of a reporter containing 3 copies of estrogen response element in COS-1 cells [13].
• Since tissue distribution of FHL2 was highly restricted to the heart, the function of FHL2 may be observed in a cell type- or promoter-specific manner [13].

Anatomical context of FHL2

• In the adult, FHL2 is expressed in the myocardium of the heart and in the epithelial cells of the prostate, where it colocalizes with the AR in the nucleus [8].
• Both FHL1 and FHL3 were expressed in a number of skeletal muscles while FHL2 was expressed at high levels in cardiac muscle [14].
• We found that FHL2 and FHL3 were colocalized in the mitochondria of the C2C12 cells and FRET was observed by using an epi-fluorescent microscope equipped with an FRET specific filter set [12].
• Northern blot analysis showed that FHL2 was strongly expressed in human osteoblasts [15].
• When the human FHL2 cDNA probe was used to hybridize with poly-A RNA of various human tissues, a very strong signal could be seen in heart tissues, and only moderately low signals could be detected in placenta, skeletal muscle and ovary [16].

Associations of FHL2 with chemical compounds

• The association of FHL2 or FHL3 with integrin receptors neither influences attachment of cells to different substrates nor changes their migration capacity [11].
• FHL2 interacted with ERalpha in the presence of 17beta-estradiol, but not of tamoxifen or raloxifene in yeast [13].
• We previously identified LSD1 and FHL2 as nuclear cofactors interacting specifically with the AR in prostate cells and showed that both stimulate androgen-dependent gene transcription [17].
• Identification of the FHL2 Transcriptional Coactivator as a New Functional Target of the E7 Oncoprotein of Human Papillomavirus Type 16 [2].
• In our study we investigated the association of pp125FAK, a cytoplasmic tyrosine kinase, involved in anchorage-independent growth of tumor cells, and the Four and a Half LIM domain (FHL) protein FHL2, which was recently shown to interact with integrins [5].

Physical interactions of FHL2

• In this report, FHL3 was shown to be a novel interacting partner of FHL2 using the yeast two-hybrid assay [12].
• BRCA1 interacts with FHL2 and enhances FHL2 transactivation function [3].
• In the yeast two-hybrid library screening, the heart-specific FHL2 protein was found to interact with hCDC47 [4].
• Focal adhesion kinase interacts with the transcriptional coactivator FHL2 and both are overexpressed in epithelial ovarian cancer [5].
• In cells, FHL2 interacts exclusively with the nonprocessed coactivator and costimulates transcription of an HCF-1-dependent target gene [18].

Regulatory relationships of FHL2

• Thus, the ability of FHL2 to stimulate the trans-activating function of beta-catenin might be dependent on the promoter context [19].
• BRCA1 enhanced FHL2-mediated transcriptional activity in transient transfections [3].
• Overall, our findings indicate that FHL2 can also regulate p53 via a direct association with HIPK2 [20].
• The functional interaction of HCF-1 with FHL2 supports a model in which site-specific proteolysis regulates the interaction of HCF-1 with protein partners and thus can modulate the activity of this coactivator [18].
• This E4F1-FHL2 association occurs in the nuclear compartment and inhibits the capacity of E4F1 to block cell proliferation [21].

Other interactions of FHL2

• Identification of the LIM protein FHL2 as a coactivator of beta-catenin [19].
• FHL2, a novel tissue-specific coactivator of the androgen receptor [8].
• In a yeast two-hybrid screen, we identified the four and a half of LIM-only protein 2 (FHL2) as a novel beta-catenin-interacting protein [19].
• ARA55 mRNA was absent in LNCaP cells, LNCaP sublines, and DU-145 cells; FHL2 was not expressed in LNCaP cells and its derivatives [22].
• These results suggest that the BRCA1-FHL2 interaction may be involved in transcriptional regulation and play a significant role in cancer cell growth [3].

Analytical, diagnostic and therapeutic context of FHL2

• FHL2 was mapped to chromosome 2q12-q13 by fluorescent in-situ hybridization (FISH) [16].
• Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart [16].
• Besides, Western blot analysis using affinity-purified anti-FHL2 antipeptide antibodies confirmed a 32-kDa protein of FHL2 in heart only [23].
• Purified recombinant FHL2 was used to generate antibodies allowing detection and immunoprecipitation of FHL2 from human cells [24].
• Both recombinant and natural FHL2 were characterized by SDS-PAGE and MALDI-TOF mass spectrometry [24].

References