In unstressed cells, spontaneous homotrimerization is inhibited. Intramolecular interactions between the hydrophobic repeat HR-A/B and HR-C regions are necessary to maintain HSF1 in the inactive, monomeric conformation. Furthermore, intramolecular interactions between the regulatory domain and the nonadjacent transactivation domain prevents transcriptional activation, a process that is relieved upon heat shock. The regulatory domain is necessary for full repression of the transcriptional activation domain in unstressed cells through its phosphorylation on Ser-303 and Ser-307. In heat stressed cells, HSF1 homotrimerization occurs through formation of a three-stranded coiled-coil structure generated by intermolecular interactions between HR-A/B regions allowing DNA-binding activity. The D domain is necessary for translocation to the nucleus, interaction with JNK1 and MAPK3 and efficient JNK1- and MAPK3-dependent phosphorylation. The regulatory domain confers heat shock inducibility on the transcriptional transactivation domain. The regulatory domain is necessary for transcriptional activation through its phosphorylation on Ser-230 upon heat shock. 9aaTAD is a transactivation motif present in a large number of yeast and animal transcription factors.
Functions as a stress-inducible and DNA-binding transcription factor that plays a central role in the transcriptional activation of the heat shock response (HSR), leading to the expression of a large class of molecular chaperones, heat shock proteins (HSPs), that protect cells from cellular insult damage. In unstressed cells, is present in a HSP90-containing multichaperone complex that maintains it in a non-DNA-binding inactivated monomeric form. Upon exposure to heat and other stress stimuli, undergoes homotrimerization and activates HSP gene transcription through binding to site-specific heat shock elements (HSEs) present in the promoter regions of HSP genes. Upon heat shock stress, forms a chromatin-associated complex with TTC5/STRAP and p300/EP300 to stimulate HSR transcription, therefore increasing cell survival. Activation is reversible, and during the attenuation and recovery phase period of the HSR, returns to its unactivated form. Binds to inverted 5'-NGAAN-3' pentamer DNA sequences. Binds to chromatin at heat shock gene promoters. Activates transcription of transcription factor FOXR1 which in turn activates transcription of the heat shock chaperones HSPA1A and HSPA6 and the antioxidant NADPH-dependent reductase DHRS2 (By similarity). Binds the promoter region upstream of exon 1 of Mpv17l to activate expression of the M-LPS isoform which is involved in metabolism of reactive oxygen species (PubMed:20231359). Also serves several other functions independently of its transcriptional activity. Involved in the repression of Ras-induced transcriptional activation of the c-fos gene in heat-stressed cells. Positively regulates pre-mRNA 3'-end processing and polyadenylation of HSP70 mRNA upon heat-stressed cells in a symplekin (SYMPK)-dependent manner. Plays a role in nuclear export of stress-induced HSP70 mRNA. Plays a role in the regulation of mitotic progression. Also plays a role as a negative regulator of non-homologous end joining (NHEJ) repair activity in a DNA damage-dependent manner. Involved in stress-induced cancer cell proliferation in a IER5-dependent manner.
Phosphorylated. Phosphorylated in unstressed cells; this phosphorylation is constitutive and implicated in the repression of HSF1 transcriptional activity. Phosphorylated on Ser-121 by MAPKAPK2; this phosphorylation promotes interaction with HSP90 proteins and inhibits HSF1 homotrimerization, DNA-binding and transactivation activities. Phosphorylation on Ser-303 by GSK3B/GSK3-beat and on Ser-307 by MAPK3 within the regulatory domain is involved in the repression of HSF1 transcriptional activity and occurs in a RAF1-dependent manner. Phosphorylation on Ser-303 and Ser-307 increases HSF1 nuclear export in a YWHAE- and XPO1/CRM1-dependent manner. Phosphorylation on Ser-307 is a prerequisite for phosphorylation on Ser-303. According to, Ser-303 is not phosphorylated in unstressed cells. Phosphorylated on Ser-415 by PLK1; phosphorylation promotes nuclear translocation upon heat shock. Hyperphosphorylated upon heat shock and during the attenuation and recovery phase period of the heat shock response. Phosphorylated on Thr-142; this phosphorylation increases HSF1 transactivation activity upon heat shock. Phosphorylation on Ser-230 by CAMK2A; this phosphorylation enhances HSF1 transactivation activity upon heat shock. Phosphorylation on Ser-326 by MAPK12; this phosphorylation enhances HSF1 nuclear translocation, homotrimerization and transactivation activities upon heat shock. Phosphorylated on Ser-320 by PRKACA/PKA; this phosphorylation promotes nuclear localization and transcriptional activity upon heat shock. Phosphorylated by MAPK8; this phosphorylation occurs upon heat shock, induces HSF1 translocation into nuclear stress bodies and negatively regulates transactivation activity. Neither basal nor stress-inducible phosphorylation on Ser-230, Ser-292, Ser-303, Ser-307, Ser-314, Ser-319, Ser-320, Thr-323, Ser-326, Ser-338, Ser-345, Ser-364 and Thr-365 within the regulatory domain is involved in the regulation of HSF1 subcellular localization or DNA-binding activity; however, it negatively regulates HSF1 transactivation activity. Phosphorylated on Ser-216 by PLK1 in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex inducing HSF1 degradation, and hence mitotic progression. Dephosphorylated on Ser-121, Ser-307, Ser-314 and Thr-323 by phosphatase PPP2CA in an IER5-dependent manner, leading to HSF1-mediated transactivation activity.
Sumoylated with SUMO1 and SUMO2 upon heat shock in a ERK2-dependent manner. Sumoylated by SUMO1 on Lys-298; sumoylation occurs upon heat shock and promotes its localization to nuclear stress bodies and DNA-binding activity. Phosphorylation on Ser-303 and Ser-307 is probably a prerequisite for sumoylation.
Acetylated on Lys-118; this acetylation is decreased in a IER5-dependent manner. Acetylated on Lys-118, Lys-208 and Lys-298; these acetylations occur in a EP300-dependent manner. Acetylated on Lys-80; this acetylation inhibits DNA-binding activity upon heat shock. Deacetylated on Lys-80 by SIRT1; this deacetylation increases DNA-binding activity.
Ubiquitinated by SCF(BTRC) and degraded following stimulus-dependent phosphorylation at Ser-216 by PLK1 in mitosis. Polyubiquitinated. Undergoes proteasomal degradation upon heat shock and during the attenuation and recovery phase period of the heat shock response.
Belongs to the HSF family.
Heat shock factor protein 1, HSF 1, Heat shock transcription factor 1, HSTF 1, Hsf1
Proteins
Oncology
57223Da
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