Cancer is characterized by uncontrolled tumour cell proliferation resulting from aberrant activity of various cell cycle proteins. Therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrate that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. By contrast, many cancers are uniquely dependent on these proteins and hence are selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. In this Review, we focus on proteins that directly regulate cell cycle progression (such as cyclin-dependent kinases (CDKs)), as well as checkpoint kinases, Aurora kinases and Polo-like kinases (PLKs). We discuss the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as the future therapeutic potential of various cell cycle inhibitors.

Cell Cycle Proteins as Promising Targets in Cancer Therapy

https://rnajc.ucsf.edu/sites/rnajc.ucsf.edu/files/cmyc.pdf

c-Myc regulates transcriptional pause release.

Gene expression in eukaryotes requires several multi-component cellular machines. Each machine carries out a separate step in the gene expression pathway, which includes transcription, several pre-messenger RNA processing steps and the export of mature mRNA to the cytoplasm. Recent studies lead to the view that, in contrast to a simple linear assembly line, a complex and extensively coupled network has evolved to coordinate the activities of the gene expression machines. The extensive coupling is consistent with a model in which the machines are tethered to each other to form 'gene expression factories' that maximize the efficiency and specificity of each step in gene expression.

http://m.docente.unife.it/franco.pagani/lezioni-1010/Maniatis%20Reed%20review%20NAture2002%20copy.pdf

An extensive network of coupling among gene expression machines

The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription.

Controlling the Elongation Phase of Transcription with P-TEFb

Flavopiridol inhibits P-TEFb and blocks HIV-1 replication.

The elongation of transcription is a highly regulated process that requires negative and positive effectors. By binding the double-stranded stem in the transactivation response (TAR) element, RD protein from the negative transcription elongation factor (NELF) inhibits basal transcription from the long terminal repeat of the human immunodeficiency virus type 1 (HIVLTR). Tat and its cellular cofactor, the positive transcription elongation factor b (P-TEFb), overcome this negative effect. Cdk9 in P-TEFb also phosphorylates RD at sites next to its RNA recognition motif. A mutant RD protein that mimics its phosphorylated form no longer binds TAR nor represses HIV transcription. In sharp contrast, a mutant RD protein that cannot be phosphorylated by P-TEFb functions as a dominant-negative effector and inhibits Tat transactivation. These results better define the transition from abortive to productive transcription and thus replication of HIV.

Dynamics of Human Immunodeficiency Virus Transcription: P-TEFb Phosphorylates RD and Dissociates Negative Effectors from the Transactivation Response Element

SARS-CoV-2 spike variants exhibit differential infectivity and neutralization resistance to convalescent or post-vaccination sera.

a o t v r C 1 p The human immunodeficiency virus type 1 (HIV-1) enodes a transcriptional transactivator called Tat (hTat) Cullen, 1998; Emerman and Malim, 1998; Frankel and oung, 1998; Gait and Karn, 1995; Gaynor, 1995; Jeang, 998; Jones, 1997; Jones and Peterlin, 1994). hTat is xpressed early in the life cycle of HIV-1 and is essential or viral gene expression, replication, and pathogenesis Dayton et al., 1986; Fisher et al., 1986). Unlike other nown eukaryotic transcriptional activators that bind to NA, hTat interacts with the transactivation response TAR; hTAR) RNA structure, which is located at the 59 end f all viral transcripts. Moreover, hTat regulates the proess of elongation rather than initiation of transcription Jones and Peterlin, 1994; Kao et al., 1987). In its absence, ranscription complexes assemble on the viral promoter LTR), but RNA polymerase II (RNAPII) synthesizes only hort transcripts (Kao et al., 1987). The binding of hTat to TAR renders the RNAPII competent for elongation (Kao t al., 1987; Laspia et al., 1989; Feinberg et al., 1991). This igh affinity interaction between hTat and hTAR is medited by the cyclin subunit of the positive elongation actor b (P-TEFb). By interacting with the human cyclin T1 hT1), hTat recruits the cyclin-dependent kinase 9 CDK9), which phosphorylates the C-terminal domain CTD) of RNAPII. The conversion of RNAPII from its nphosphorylated (RNAPIIa) to phosphorylated (RNAIIo) forms marks the transition from initiation to elongaion of transcription (Jones, 1997). This review begins with structures of hTat and hTAR. ext, we present genetic and biochemical evidence that ed to the current model of hTat transactivation. After a iscussion of other lentiviral Tat proteins, which recruit -TEFb by slightly different mechanisms, Tat transactivaion is placed into the context of eukaryotic transcription.

Ran Taube

Papers

Flavopiridol inhibits P-TEFb and blocks HIV-1 replication.

Dynamics of Human Immunodeficiency Virus Transcription: P-TEFb Phosphorylates RD and Dissociates Negative Effectors from the Transactivation Response Element

SARS-CoV-2 spike variants exhibit differential infectivity and neutralization resistance to convalescent or post-vaccination sera.

MINIREVIEW Tat Transactivation: A Model for the Regulation of Eukaryotic Transcriptional Elongation

Tat transactivation: a model for the regulation of eukaryotic transcriptional elongation.