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HLF  -  hepatic leukemia factor

Homo sapiens

Synonyms: Hepatic leukemia factor, MGC33822
 
 
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Disease relevance of HLF

 

High impact information on HLF

  • Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor [5].
  • The E2A-HLF (for hepatic leukaemia factor) fusion gene, formed by action of the t(17;19) (q22;p13) chromosomal translocation, drives the leukaemic transformation of early B-cell precursors, but the mechanism of this activity remains unknown [5].
  • The chimeric protein consisted of the amino-terminal transactivation domain of E2A linked to the carboxyl-terminal basic region-leucine zipper domain of HLF [6].
  • A t(17;19) chromosomal translocation in early B-lineage acute leukemia was shown to result in chimeric transcripts that contain sequences from the E2A basic helix-loop-helix transcription factor gene on chromosome 19, fused to sequences from a previously unidentified gene (HLF) on chromosome 17 that encodes a hepatic leukemia factor [6].
  • Hlf, which is not normally transcribed in lymphoid cells, belongs to the recently described PAR subfamily of basic leucine zipper (bZIP) proteins, which also includes Dbp and Tef/Vbp [7].
 

Chemical compound and disease context of HLF

 

Biological context of HLF

  • We previously reported that the E2A-HLF fusion protein protects interleukin-3 (IL-3)-dependent lymphoid cells from apoptosis caused by cytokine starvation [1].
  • TEF and HLF activated transcription of consensus site-containing reporter genes in several different cell types with similar potencies [11].
  • Using a binding site selection assay, we found that TEF bound preferentially to the consensus sequence 5'-GTTACGTAAT-3', which is identical to the previously determined HLF recognition site [11].
  • The proto-oncogene HLF and the related basic leucine zipper protein TEF display highly similar DNA-binding and transcriptional regulatory properties [11].
  • Since neither DNA binding nor protein dimerization through the bZIP domain of HLF is required for this effect, we propose mechanisms whereby protein-protein interactions with the amino-terminal region of E2A allow the chimera to act as a transcriptional cofactor to alter the expression of genes regulating the apoptotic machinery in pro-B cells [12].
 

Anatomical context of HLF

  • Interestingly, wild-type HLF was restricted in its capacity to act as a trans activator, functioning in human fetal kidney cells but not HepG2 hepatocarcinoma cells or NIH 3T3 mouse fibroblasts [13].
  • The ability of the E2A-HLF hybrid protein to bind DNA in a sequence-specific manner and trans activate the expression of artificial reporter genes suggests that it could subvert transcriptional programs that normally control the growth, differentiation, and survival of lymphoid progenitor cells [13].
  • Expression of E2A-HLF chimeric protein induced T-cell apoptosis, B-cell maturation arrest, and development of acute lymphoblastic leukemia [4].
  • ABCB1 over-expression and drug-efflux in acute lymphoblastic leukemia cell lines with t(17;19) and E2A-HLF expression [14].
  • When cells were cultured in the presence of 12-O-tetradecanoylphorbol-13-acetate, significant amounts of IL6 were detected in the culture supernatants of Chang liver cells, HLF cells, and HLE cells [15].
 

Associations of HLF with chemical compounds

  • HLF is capable of binding to multiple sites in both the Factor VIII and Factor IX promoters [2].
  • 5-FU had synergistic effect on TRAIL in HLF and additive effect in four other HCC cell lines [16].
  • Troglitazone increased p27(Kip1) in time- and dose-dependent manners, suggesting that p27(Kip1) may be involved in the growth inhibition by troglitazone in HLF cells [17].
  • However, using a preloading assay, transfer of calcein was observed between donor HLF cells and first order neighboring recipient tumor cells (recipient cells in 1000-fold excess) [18].
  • Not only troglitazone but pioglitazone dose-dependently inhibited cell growth in HepG2 and HLF cells [17].
 

Physical interactions of HLF

  • These differences were directly attributable to loss of an HLF ancillary DNA-binding domain in all E2A-HLF chimeras and were further exacerbated by a zipper mutation in one isolate [3].
  • Wild-type Hlf is able to bind DNA specifically as a homodimer or as a heterodimer with other PAR factors [7].
 

Regulatory relationships of HLF

  • These findings indicate that E2A-HLF induces annexin II by substituting for cytokines that activate downstream pathways of Ras [1].
  • These findings establish a spectrum of binding site-specific transcriptional properties for E2A-HLF which may preferentially activate expression of select subordinate genes as a homodimer and potentially antagonize expression of others through heteromeric interactions [3].
 

Other interactions of HLF

  • To address these questions, we cloned the human homologue of TEF/VBP, a bZIP protein closely related to HLF [11].
  • Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein [1].
  • Enhanced binding of HLF/DBP heterodimers represents one mechanism of PAR protein transactivation of the factor VIII and factor IX genes [2].
  • Since the E2A, PBX1 and HLF proteins all appear to function as transcription factors, it appears likely that the oncogenic fusion proteins contribute to leukemia development by causing abnormal transcriptional regulation of key target genes [19].
  • E2A-HLF acts as a transcriptional activator and E4BP4 as a transcriptional repressor [20].
 

Analytical, diagnostic and therapeutic context of HLF

References

  1. Regulation of annexin II by cytokine-initiated signaling pathways and E2A-HLF oncoprotein. Matsunaga, T., Inaba, T., Matsui, H., Okuya, M., Miyajima, A., Inukai, T., Funabiki, T., Endo, M., Look, A.T., Kurosawa, H. Blood (2004) [Pubmed]
  2. Enhanced binding of HLF/DBP heterodimers represents one mechanism of PAR protein transactivation of the factor VIII and factor IX genes. Begbie, M., Mueller, C., Lillicrap, D. DNA Cell Biol. (1999) [Pubmed]
  3. DNA-binding and transcriptional regulatory properties of hepatic leukemia factor (HLF) and the t(17;19) acute lymphoblastic leukemia chimera E2A-HLF. Hunger, S.P., Brown, R., Cleary, M.L. Mol. Cell. Biol. (1994) [Pubmed]
  4. Expression of E2A-HLF chimeric protein induced T-cell apoptosis, B-cell maturation arrest, and development of acute lymphoblastic leukemia. Honda, H., Inaba, T., Suzuki, T., Oda, H., Ebihara, Y., Tsuiji, K., Nakahata, T., Ishikawa, T., Yazaki, Y., Hirai, H. Blood (1999) [Pubmed]
  5. Reversal of apoptosis by the leukaemia-associated E2A-HLF chimaeric transcription factor. Inaba, T., Inukai, T., Yoshihara, T., Seyschab, H., Ashmun, R.A., Canman, C.E., Laken, S.J., Kastan, M.B., Look, A.T. Nature (1996) [Pubmed]
  6. Fusion of the leucine zipper gene HLF to the E2A gene in human acute B-lineage leukemia. Inaba, T., Roberts, W.M., Shapiro, L.H., Jolly, K.W., Raimondi, S.C., Smith, S.D., Look, A.T. Science (1992) [Pubmed]
  7. Hlf, a novel hepatic bZIP protein, shows altered DNA-binding properties following fusion to E2A in t(17;19) acute lymphoblastic leukemia. Hunger, S.P., Ohyashiki, K., Toyama, K., Cleary, M.L. Genes Dev. (1992) [Pubmed]
  8. One hundred sixteen cases of acute liver failure treated with MARS. Novelli, G., Rossi, M., Pretagostini, M., Pugliese, F., Ruberto, F., Novelli, L., Nudo, F., Bussotti, A., Corradini, S., Martelli, S., Berloco, P.B. Transplant. Proc. (2005) [Pubmed]
  9. Optimisation of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy with a new schedule of hydroxyurea, leucovorin, 5-FU and cisplatin (HLFP regimen) for metastatic oesophageal cancer. Taïeb, J., Artru, P., Baujat, B., Mabro, M., Carola, E., Maindrault, F., Tournigand, C., Krulik, M., Louvet, C., de Gramont, A. Eur. J. Cancer (2002) [Pubmed]
  10. Prognostic factor analysis in advanced gastric cancer patients treated with hydroxyurea, leucovorin, 5-fluorouracil, and cisplatin (HLFP regimen). Louvet, C., Carrat, F., Mal, F., Mabro, M., Beerblock, K., Vaillant, J.C., Cady, J., André, T., Gamelin, E., de Gramont, A. Cancer Invest. (2003) [Pubmed]
  11. The proto-oncogene HLF and the related basic leucine zipper protein TEF display highly similar DNA-binding and transcriptional regulatory properties. Hunger, S.P., Li, S., Fall, M.Z., Naumovski, L., Cleary, M.L. Blood (1996) [Pubmed]
  12. The AD1 and AD2 transactivation domains of E2A are essential for the antiapoptotic activity of the chimeric oncoprotein E2A-HLF. Inukai, T., Inaba, T., Ikushima, S., Look, A.T. Mol. Cell. Biol. (1998) [Pubmed]
  13. DNA-binding specificity and trans-activating potential of the leukemia-associated E2A-hepatic leukemia factor fusion protein. Inaba, T., Shapiro, L.H., Funabiki, T., Sinclair, A.E., Jones, B.G., Ashmun, R.A., Look, A.T. Mol. Cell. Biol. (1994) [Pubmed]
  14. ABCB1 over-expression and drug-efflux in acute lymphoblastic leukemia cell lines with t(17;19) and E2A-HLF expression. Baudis, M., Prima, V., Tung, Y.H., Hunger, S.P. Pediatric blood & cancer. (2006) [Pubmed]
  15. Production of interleukin 6 from human liver cell lines: production of interleukin 6 is not concurrent with the production of alpha-fetoprotein. Matsuguchi, T., Okamura, S., Kawasaki, C., Niho, Y. Cancer Res. (1990) [Pubmed]
  16. Partial contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/TRAIL receptor pathway to antitumor effects of interferon-alpha/5-fluorouracil against Hepatocellular Carcinoma. Yamamoto, T., Nagano, H., Sakon, M., Wada, H., Eguchi, H., Kondo, M., Damdinsuren, B., Ota, H., Nakamura, M., Wada, H., Marubashi, S., Miyamoto, A., Dono, K., Umeshita, K., Nakamori, S., Yagita, H., Monden, M. Clin. Cancer Res. (2004) [Pubmed]
  17. Growth arrest by troglitazone is mediated by p27Kip1 accumulation, which results from dual inhibition of proteasome activity and Skp2 expression in human hepatocellular carcinoma cells. Motomura, W., Takahashi, N., Nagamine, M., Sawamukai, M., Tanno, S., Kohgo, Y., Okumura, T. Int. J. Cancer (2004) [Pubmed]
  18. Effective asymmetry in gap junctional intercellular communication between populations of human normal lung fibroblasts and lung carcinoma cells. Zhang, Z.Q., Hu, Y., Wang, B.J., Lin, Z.X., Naus, C.C., Nicholson, B.J. Carcinogenesis (2004) [Pubmed]
  19. E2A basic helix-loop-helix transcription factors in human leukemia. LeBrun, D.P. Front. Biosci. (2003) [Pubmed]
  20. E4BP4 expression is regulated by the t(17;19)-associated oncoprotein E2A-HLF in pro-B cells. Yeung, J., O'Sullivan, E., Hubank, M., Brady, H.J. Br. J. Haematol. (2004) [Pubmed]
  21. E2A/HLF fusion gene in an acute lymphoblastic leukemia patient with disseminated intravascular coagulation and a normal karyotype. Dahéron, L., Brizard, F., Millot, F., Cividin, M., Lacotte, L., Guilhot, F., Brizard, A. Hematol. J. (2002) [Pubmed]
  22. Expression patterns of the hepatic leukemia factor gene in the nervous system of developing and adult mice. Hitzler, J.K., Soares, H.D., Drolet, D.W., Inaba, T., O'Connel, S., MG Rosenfeld, n.u.l.l., Morgan, J.I., Look, A.T. Brain Res. (1999) [Pubmed]
  23. Activation of Galectin-1 gene in human hepatocellular carcinoma involves methylation-sensitive complex formations at the transcriptional upstream and downstream elements. Kondoh, N., Hada, A., Ryo, A., Shuda, M., Arai, M., Matsubara, O., Kimura, F., Wakatsuki, T., Yamamoto, M. Int. J. Oncol. (2003) [Pubmed]
  24. Cardiac output augmentation during hypoxemia improves cerebral metabolism after hypothermic cardiopulmonary bypass. Schultz, J.M., Karamlou, T., Shen, I., Ungerleider, R.M. Ann. Thorac. Surg. (2006) [Pubmed]
 
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