The RB C-terminal domain is required for high-affinity binding to E2F-DP complexes and for maximal repression of E2F-responsive promoters, thereby acting as a growth suppressor by blocking the G1-S transition of the cell cycle. This domain has a strand-loop-helix structure, which directly interacts with both E2F1 and DP1, followed by a tail segment that lacks regular secondary structure [].
Cell division cycle-associated protein 7 (CDCA7/JPO1) is a transcription regulator whose expression is activated by c-Myc and by E2F1 []. CDCA7 can associate with Myc in a phosphorylation-dependent manner. CDCA7 phosphorylation by AKT leads to loss of its association with Myc []. This interaction affects Myc-dependent apoptosis and transformation [, , ]. CDCA7 has also been identified as a Notch target involved in hematopoietic stem cell emergence [].
This group represents adenoviral early E1A proteins. The E1A protein is responsible for the transcriptional activation of the early genes with in the viral genome at the start of the infection process as well as some cellular genes [].E1A disrupts the function of host retinoblastoma protein RB1/pRb, which is a key regulator of the cell cycle []. It also induces the disassembly of the E2F1 transcription factors from RB1 by direct competition for the same binding site on RB1, with subsequent transcriptional activation of E2F1-regulated S-phase genes []. Inactivation of the ability of RB1 to arrest the cell cycle is critical for cellular transformation, uncontrolled cellular growth and proliferation induced by viral infection. The stimulation of the progression from G1 to S phase allows the virus to efficiently use the cellular DNA replicating machinery to achieve viral genome replication.
This entry includes Host cell factor 1 (HCF1) and Host cell factor 2 (HCF2) from humans. They contain an N-terminal kelch domain and a C-terminal FnIII domain. However, HCF2 is smaller than HCF-1, lacking the complete central region including the HCF1 specific repeats and as a result is not subject to proteolytic processing []. This entry also includes their Drosophila melanogaster homologue, dHCF, which is involved in both activation and repression of transcription during fly development []. Host cell factor homologue hcf-1 from C. elegans controls the cell cycle through mitotic histone phosphorylation modulation and negatively regulates responses to environmental stresses [].HCF1 is associated with the activation and repression of gene expression. It is brought to specific promoters by association with DNA-sequence-specific transcription factors such as Sp1, GABP, YY1, Ronin/THAP11, and E2F1 and E2F4 []. HCFC1 recruits and is a part of several different complexes, including the SET1 histone methyltransferase complex (transcription activation), the SIN3 histone deacetylase complex (transcription repression) [], the THAP1/THAP3-HCFC1-OGT complex (required for the regulation of the transcriptional activity of RRM1) [], and the NSL complex (acetylation of nucleosomal histone H4) [].HCF2 is involved in activation of differentiation and morphogenesis gene expression programs, and in parallel in inhibition of cellular growth and metabolism [].
Host cell factor 1 (HCFC1) is associated with the activation and repression of gene expression. It is brought to specific promoters by association with DNA-sequence-specific transcription factors such as Sp1, GABP, YY1, Ronin/THAP11, and E2F1 and E2F4 []. HCFC1 recruits and is a part of several different complexes, including the SET1 histone methyltransferase complex (transcription activation), the SIN3 histone deacetylase complex (transcription repression) [], the THAP1/THAP3-HCFC1-OGT complex (required for the regulation of the transcriptional activity of RRM1) [], and the NSL complex (acetylation of nucleosomal histone H4) []. This entry includes mammalian HCFC1 and the Drosophila homologue, dHCF. They undergo a process of proteolytic maturation to produce a heterodimeric complex of HCF-N and HCF-C subunits, by different enzymes, O-GlcNAc transferase and taspase1, respectively [, ]. They share a Kelch domain, regions biased for basic (Basic) or acidic (Acidic) amino acids, fibronectin type 3 repeats, and a nuclear localization signal [].During human herpes simplex virus infection, HCFC1 forms a multiprotein-DNA complex enabling transcription of the virus's early genes []. It is also a co-activator of EGR2/Krox20 []and the GA-binding protein GABP2 [], and represses ZBTB17/Miz-1 [].
The entry represents the UBA domain found in c-IAPs, including BIRC2 (also known as C-IAP1) and BIRC3 (also known as C-IAP2). c-IAPs function as ubiquitin E3 ligases that mediate the ubiquitination of the substrates involved in apoptosis, nuclear factor-kappaB (NF-kappaB) signaling, and oncogenesis [, ]. Unlike other apoptosis proteins such as XIAP, c-IAPs exhibit minimal binding to caspases and may not play an important role in the inhibition of these proteases. c-IAP1 is a potent regulator of the tumor necrosis factor (TNF) receptor family and NF-kappaB signaling pathways in the cytoplasm. It can also regulate E2F1 transcription factor-mediated control of cyclin transcription in the nucleus []. c-IAP2 also influences ubiquitin-dependent pathways that modulate innate immune signalling by activation of NF-kappaB []. c-IAPs contain three N-terminal baculoviral IAP repeat (BIR) domains that enable interactions with proteins, a ubiquitin-association (UBA) domain that is responsible for the binding of polyubiquitin (polyUb), a caspase activation and recruitment domain (CARD) that serves as a protein interaction surface, and a RING domain at the carboxyl terminus that is required for ubiquitin ligase activity [, ].
This entry includes CDCA7 and CDA7L.Cell division cycle-associated protein 7 (CDCA7/JPO1) is a transcription regulator whose expression is activated by c-Myc and by E2F1 []. CDCA7 can associate with Myc in a phosphorylation-dependent manner. CDCA7 phosphorylation by AKT leads to loss of its association with Myc []. This interaction affects Myc-dependent apoptosis and transformation [, , ]. CDCA7 has also been identified as a Notch target involved in hematopoietic stem cell emergence [].Cell division cycle-associated 7-like protein (CDCA7L/JPO2/R1) is closely related to CDCA7/JPO1; and like CDCA7, it plays a role in transcriptional regulation and interacts with c-Myc []. JPO2 overexpression induces metastasis in medulloblastoma []. JPO2 can interact directly and dynamically with chromatin, the dynamics of JPO2 chromatin binding being decelerated upon interaction with LEDGF/p75, which binds and tethers JPO2 to chromatin [, ].JPO2 inhibits monoamine oxidase A (MAOA) activity and gene expression by binding to the promoter []. JPO2 and MAOA act upstream of cyclin D1 and E2F1, and are involved in apoptotic signalling pathways [].
