HSF1

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HSF1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases HSF1, HSTF1, heat shock transcription factor 1
External IDs MGI: 96238 HomoloGene: 74556 GeneCards: HSF1
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005526

NM_008296

RefSeq (protein)

NP_005517

NP_001318081
NP_001318082
NP_001318083
NP_001318143
NP_032322

Location (UCSC) Chr 8: 144.29 – 144.31 Mb Chr 15: 76.48 – 76.5 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Heat shock factor 1 (HSF1) is a protein that in humans is encoded by the HSF1 gene.[3] HSF1 is highly conserved in eukaryotes and is the primary mediator of transcriptional responses to proteotoxic stress with important roles in non-stress regulation such as development and metabolism.[4]

Structure[edit]

Human HSF1 consists of several domains which regulate its binding and activity.

HSF1 Domain Cartoon.jpg

DNA-Binding Domain (DBD)[edit]

This N-terminal domain of approximately 100 amino acids is the most highly conserved region in the HSF protein family and consists of a helix-turn-helix loop. The DBD of each HSF1 monomer recognizes the sequence nGAAn on target DNA. Repeated sequences of the nGAAn pentamer constitute heat shock elements (HSEs) for active HSF1 trimers to bind.[5]

Oligomerization Domain (Leucine Zipper Domains)[edit]

The two regions responsible for oligomerization between HSF1 monomers are leucine zipper (LZ) domains 1-3 and 4[6] (these regions are also commonly referred to as HR-A/B and HR-C).[5] LZ1-3 is situated just downstream of the DBD while LZ4 is located between the RD and the C-terminal TAD. Under non-stress conditions, spontaneous HSF1 activation is negatively regulated by the interaction between LZ1-3 and LZ4. When induced by stress, the LZ1-3 region breaks away from the LZ4 region and forms a trimer with other HSF1 LZ1-3 domains to form a triple coiled-coil.[6]

Regulatory Domain (RD)[edit]

The structures of the C-terminal RD and TAD of HSF1 have not been clearly resolved due to their dynamic nature.[7] However, it is known that the RD is situated between the two regions of the oligomerization domain. The RD has been shown to regulate the TAD through negative control by repressing TAD in the absence of stress, a role that is inducibly regulated through posttranslational modifications.[5][6]

Trans-Activation Domain (TAD)[edit]

This C-terminal region spans the last 150 amino acids of the HSF1 protein and contains 2 TADs (TAD1 and TAD2). TAD1, which sits at amino acids 401-420, is largely hydrophobic and is predicted to take on an alpha-helical conformation. TAD1 has been shown to directly interact with target DNA to direct HSF1's transcriptional activation. The structure of TAD2, amino acids 431-529, is not expected to be helical as it contains proline residues in addition to hydrophobic and acidic ones.[5] The function of the HSF1 TAD is still largely uncharacterized, but Hsp70 has been shown to bind with this domain, which could describe the mechanism by which Hsp70 negatively regulates HSF1.[6]

Function[edit]

The HSF1 protein regulates the heat shock response (HSR) pathway in humans by acting as the major transcription factor for heat shock proteins. The HSR plays a protective role by ensuring proper folding and distribution of proteins within cells. This pathway is induced by not only temperature stress, but also by a variety of other stressors such as hypoxic conditions and exposure to contaminants.[6] HSF1 transactivates genes for many cytoprotective proteins involved in heat shock, DNA damage repair, and metabolism. This illustrates the versatile role of HSF1 in not only the heat shock response, but also in aging and diseases.[6]

Mechanism of action[edit]

Under non-stress conditions, HSF1 exists primarily as an inactive monomer located throughout the nucleus and the cytoplasm. In its monomeric form, HSF1 activation is repressed by interaction with chaperones such as heat shock proteins Hsp70 and Hsp90, and TRiC/CCT.[6][8] In the event of proteotoxic stress such as heat shock, these chaperones are released from HSF1 to perform their protein-folding roles; simultaneously, the exportation of HSF1 to the cytoplasm is inhibited. These actions allow HSF1 to trimerize and accumulate in the nucleus to stimulate transcription of target genes.[5][6][9]

Clinical significance[edit]

HSF1 is a promising drug target in cancer and proteopathy.[10]

The genes activated by HSF1 under heat shock conditions have been recently shown to differ from those activated in malignant cancer cells, and this cancer-specific HSF1 panel of genes has indicated poor prognosis in breast cancer. The ability of cancer cells to use HSF1 in a unique manner gives this protein significant clinical implications for therapies and prognoses.[11]

In the case of protein-folding diseases such as Huntington's disease (HD), however, induction of the heat shock response pathway would prove beneficial. In recent years, using cells that express the poly-glutamine expansion found in HD, it has been shown that both the HSR and HSF1 levels are reduced after heat shock. This reduced ability of diseased cells to respond to stress helps to explain the toxicity associated with certain diseases.[12]

Interactions[edit]

HSF1 has been shown to interact with:

CEBPB,[13] HSF2,[14] HSPA1A,[15][16] HSPA4,[17][18] Heat shock protein 90kDa alpha (cytosolic) member A1,[19][17] NCOA6,[20] RALBP1[19] and SYMPK.[21]

See also[edit]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ Rabindran SK, Giorgi G, Clos J, Wu C (August 1991). "Molecular cloning and expression of a human heat shock factor, HSF1". Proceedings of the National Academy of Sciences of the United States of America. 88 (16): 6906–10. PMC 52202Freely accessible. PMID 1871105. doi:10.1073/pnas.88.16.6906. 
  4. ^ Vihervaara A, Sistonen L (January 2014). "HSF1 at a glance". Journal of Cell Science. 127 (Pt 2): 261–6. PMID 24421309. doi:10.1242/jcs.132605. 
  5. ^ a b c d e Anckar J, Sistonen L (2011-06-15). "Regulation of HSF1 function in the heat stress response: implications in aging and disease". Annual Review of Biochemistry. 80 (1): 1089–115. PMID 21417720. doi:10.1146/annurev-biochem-060809-095203. 
  6. ^ a b c d e f g h Dayalan Naidu S, Dinkova-Kostova AT (January 2017). "Regulation of the mammalian heat shock factor 1". The FEBS Journal: n/a–n/a. PMID 28052564. doi:10.1111/febs.13999. 
  7. ^ Neudegger T, Verghese J, Hayer-Hartl M, Hartl FU, Bracher A (February 2016). "Structure of human heat-shock transcription factor 1 in complex with DNA". Nature Structural & Molecular Biology. 23 (2): 140–6. PMID 26727489. doi:10.1038/nsmb.3149. 
  8. ^ "Entrez Gene: HSF1 heat shock transcription factor 1". 
  9. ^ Shamovsky I, Nudler E (March 2008). "New insights into the mechanism of heat shock response activation". Cellular and Molecular Life Sciences. 65 (6): 855–61. PMID 18239856. doi:10.1007/s00018-008-7458-y. 
  10. ^ Anckar J, Sistonen L (March 2011). "Regulation of HSF1 function in the heat stress response: implications in aging and disease". Annual Review of Biochemistry. 80: 1089–115. PMID 21417720. doi:10.1146/annurev-biochem-060809-095203. 
  11. ^ Mendillo ML, Santagata S, Koeva M, Bell GW, Hu R, Tamimi RM, Fraenkel E, Ince TA, Whitesell L, Lindquist S (August 2012). "HSF1 drives a transcriptional program distinct from heat shock to support highly malignant human cancers". Cell. 150 (3): 549–62. PMC 3438889Freely accessible. PMID 22863008. doi:10.1016/j.cell.2012.06.031. 
  12. ^ Chafekar SM, Duennwald ML (2012-05-23). "Impaired heat shock response in cells expressing full-length polyglutamine-expanded huntingtin". PloS One. 7 (5): e37929. PMC 3359295Freely accessible. PMID 22649566. doi:10.1371/journal.pone.0037929. 
  13. ^ Xie Y, Chen C, Stevenson MA, Auron PE, Calderwood SK (April 2002). "Heat shock factor 1 represses transcription of the IL-1beta gene through physical interaction with the nuclear factor of interleukin 6". The Journal of Biological Chemistry. 277 (14): 11802–10. PMID 11801594. doi:10.1074/jbc.M109296200. 
  14. ^ He H, Soncin F, Grammatikakis N, Li Y, Siganou A, Gong J, Brown SA, Kingston RE, Calderwood SK (September 2003). "Elevated expression of heat shock factor (HSF) 2A stimulates HSF1-induced transcription during stress". The Journal of Biological Chemistry. 278 (37): 35465–75. PMID 12813038. doi:10.1074/jbc.M304663200. 
  15. ^ Shi Y, Mosser DD, Morimoto RI (March 1998). "Molecular chaperones as HSF1-specific transcriptional repressors". Genes & Development. 12 (5): 654–66. PMC 316571Freely accessible. PMID 9499401. doi:10.1101/gad.12.5.654. 
  16. ^ Zhou X, Tron VA, Li G, Trotter MJ (August 1998). "Heat shock transcription factor-1 regulates heat shock protein-72 expression in human keratinocytes exposed to ultraviolet B light". The Journal of Investigative Dermatology. 111 (2): 194–8. PMID 9699716. doi:10.1046/j.1523-1747.1998.00266.x. 
  17. ^ a b Nair SC, Toran EJ, Rimerman RA, Hjermstad S, Smithgall TE, Smith DF (December 1996). "A pathway of multi-chaperone interactions common to diverse regulatory proteins: estrogen receptor, Fes tyrosine kinase, heat shock transcription factor Hsf1, and the aryl hydrocarbon receptor". Cell Stress & Chaperones. 1 (4): 237–50. PMC 376461Freely accessible. PMID 9222609. doi:10.1379/1466-1268(1996)001<0237:apomci>2.3.co;2. 
  18. ^ Abravaya K, Myers MP, Murphy SP, Morimoto RI (July 1992). "The human heat shock protein hsp70 interacts with HSF, the transcription factor that regulates heat shock gene expression". Genes & Development. 6 (7): 1153–64. PMID 1628823. doi:10.1101/gad.6.7.1153. 
  19. ^ a b Hu Y, Mivechi NF (May 2003). "HSF-1 interacts with Ral-binding protein 1 in a stress-responsive, multiprotein complex with HSP90 in vivo". The Journal of Biological Chemistry. 278 (19): 17299–306. PMID 12621024. doi:10.1074/jbc.M300788200. 
  20. ^ Hong S, Kim SH, Heo MA, Choi YH, Park MJ, Yoo MA, Kim HD, Kang HS, Cheong J (February 2004). "Coactivator ASC-2 mediates heat shock factor 1-mediated transactivation dependent on heat shock". FEBS Letters. 559 (1-3): 165–70. PMID 14960326. doi:10.1016/S0014-5793(04)00028-6. 
  21. ^ Xing H, Mayhew CN, Cullen KE, Park-Sarge OK, Sarge KD (March 2004). "HSF1 modulation of Hsp70 mRNA polyadenylation via interaction with symplekin". The Journal of Biological Chemistry. 279 (11): 10551–5. PMID 14707147. doi:10.1074/jbc.M311719200. 

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.