Page 241 - Williams Hematology ( PDFDrive )

216 Part IV: Molecular and Cellular Hematology Chapter 16: Cell-Cycle Regulation and Hematologic Disorders 217

etc.), forming a central node in a complex signaling network that gov- specific cdk(s), it is now clear that in addition to cell cycle-regulatory
erns the overall transcriptional and biologic response of cells to activa- cdks, transcription-regulatory cdks, such as cdk9, represent another
tion or inhibition of the kinases. 61 class of therapeutic targets. In addition, P-TEFb forms a complex with
Cdk7 plays dual functions in regulation of cell cycle and gene tran- the HIV tat protein that binds the transactivation response element.
scription. In the former case, cdk7, together with its partner cyclin H, The modification of RNA polymerase II by cdk9/cyclin T facilitates the
78
acts as a cdk-activating kinase, which fully activates various cell-cycle– efficient multiplication of the viral genome. Other binding partners
79
regulatory cdks (e.g., cdk1, cdk2, cdk4, and cdk6) by phosphorylating of cdk9 include tumor necrosis factor receptor-associated factor 2, as
80
62
their T loop in a context-specific manner. For example, whereas cdk7 well as inhibitory MAQ1 (or HEXIM1) and 7SK small nuclear RNA.
is required to determine cyclin specificity and activation order of cdc1 Furthermore, cdk9 is expressed throughout the cell cycle and is also
81
and cdk2 during S and G phases, it is also required to maintain the involved in viral (HIV, herpes) replication. 27
2
activity of cdk4 as cells exiting quiescence and G progression through Other members of the transcription-regulatory cdk subfam-
1
63
the restriction point. Cdk7, as a component of the general transcrip- ily include cdk8 and cdk12. Cdk8 is a subunit of the large Mediator
tion factor TFIIH (cdk7/cyclin H/Mat1 complex), phosphorylates the complex (~1.2 MDa) composed of 25 to 30 proteins, which acts as a
carboxy-terminal domain (CTD, serines 5 and 7) of RNA polymerase II, molecular bridge between DNA-binding transcription factors and RNA
which is responsible for transcription initiation and promoter clearance, polymerase II. Cdk8 binds to cyclin C, MED12, and MED13 in the
a critical step in switching initiation to elongation during transcrip- cyclin C–cdk8 module of the Mediator. The cdk8/cyclin C pair facili-
82
64
tion. As transcription factors that co-opt the general transcriptional tates phosphorylation of both serine 2 and serine 5 at the CTD of RNA
83
machinery to sustain the oncogenic state, pharmacologic inhibition of polymerase II. Cdk8 can perform both positive and negative functions
cdk7 may represent a novel approach to treat tumor types (e.g., T-cell in transcriptional regulation during different transcription stages (e.g.,
acute lymphoblastic leukemia [T-ALL]) that are particularly dependent preinitiation and elongation), which provide a mechanism to respond to
on transcription. 65 different promoter contexts (e.g., transcription factors or cdk8 module
Cdk9, as a catalytic subunit, partners with the regulatory sub- binding). Unlike cdk7 and cdk9, which govern global gene expression,
82
unit cyclin T, an 87-kDa cyclin C–related protein with three isoforms, cdk8 promotes only gene-specific transcription. Recently, cdk8 expres-
to form a complex known as positive transcription elongation fac- sion has been detected in 70 percent colorectal cancers and correlated
66
tor b (P-TEFb). The so-called cdk9-related pathway consists of two with β-catenin activation, suggesting that cdk8 may act as a oncogene
cdk9 isoforms (cdk9–42 and cdk9–55), cyclin T , cyclin T , cyclin T , in certain types of cancer (e.g., colorectal and pancreatic cancer). 84,85
2b
2a
1
27
and cyclin K. Cdk9 and its binding partner cyclin T comprise the Cdk12 and cdk13 have been identified as CTD kinases, both of which
1
67
P-TEFb. P-TEFb hyperphosphorylates the CTD (primarily serine 2) of are unusually large proteins that contain a central kinase domain and
86
RNA polymerase II, essential for transcription elongation. P-TEFb also share the same partner, cyclin K. Cdk12/cyclin K phosphorylates the
1
87
phosphorylates the negative transcription elongation factors (N-TEFs), CTD (preferably serine 2) of RNA polymerase II. Interestingly, cdk12/
including DRB-sensitivity inducing factor (DSIF) and the negative cyclin K only regulates expression of a small subset of genes, predom-
elongation factor (NELF), to release the transcription block (a pause inantly long genes with high exon numbers and DDR genes, includ-
immediately after transcription initiation) of both N-TEFs on hypoph- ing critical regulators of genomic stability, for example, BRCA1, ATR
osphorylated forms of RNA polymerase II. In addition, cdk9 also plays a (ataxia-telangiectasia mutated [ATM] and Rad3 related), FANCI, and
role in ribosomal RNA processing through activation of RNA polymerase FANCD2. 88
68
II. In normal cells, the activity of P-TEFb is stringently maintained The cdk10 gene encodes two different cdk-like putative kinases;
in a functional equilibrium to accommodate transcriptional demands it is postulated that they exert their function at the G /M transition.
29
2
69
for different biologic activities. As a rule in oncogenic transformation, These two isoforms predominate in human tissues, except in brain and
upregulated antiapoptotic or prosurvival proteins in transformed cells muscle, and the relative isoform levels do not vary during the cell cycle.
29
must be sustained by constitutive RNA polymerase II activity that gov- Cdk10 interacts with the N-terminus of the Ets2 transcription factor,
erns transcription elongation, in which cdk9 is the primary processivity which contains the highly conserved pointed transactivation domain.
factor. In other words, transformed cells are addicted to transcription The pointed domain is implicated in protein–protein interactions and
70
because of the requirement for continuous production of antiapoptotic Ets2 requires an intact pointed domain to bind Cdk10, which inhibits
proteins, particularly those with short half-lives. Of note, abnormal Ets2 transactivation in mammalian cells. This could be an important
31
activities in the cdk9-related pathway occur in many human malignan- factor for the development of follicular lymphoma, because cdk10 is
89
cies. For example, high levels of cdk9/cyclin T expression are found overexpressed in this cancer. In addition, cdk10 silencing increases
71
1
in several types of hematologic malignancies, including B- and T-cell Ets2-driven transcription of c-RAF, resulting in mitogen-activated pro-
precursor-derived lymphomas, anaplastic large cell lymphoma, and fol- tein kinase (MAPK) pathway activation and loss of tumor cell reliance
licular lymphomas, whereas strong nuclear staining for both proteins upon estrogen signaling. Cdk10 promoters are frequently hypermeth-
90
are observed in Hodgkin and Reed-Sternberg cells of classical Hodgkin ylated in malignant tumors, resulting in low expression levels of cdk10
lymphoma. In this context, selective cdk9 inhibitors preferentially target and impaired cell-cycle regulation. 90
91
malignant cells in preclinical hematologic tumor models, including leu- Cdk11 is associated with cyclin L. It is part of the large family
kemia and multiple myeloma. 72,73 Mcl-1, the Bcl-2 family antiapoptotic of p34(cdc2)-related kinases whose functions appear to be linked with
protein with an estimated half-life of less than 3 hours, represents one cell-cycle progression, tumorigenesis, and apoptotic signaling. Cdk11
74
of the most common downstream targets for cdk9 inhibition. More- interacts with the p47 subunit of eukaryotic initiation factor 3 during
75
over, cdk9 inhibition disrupts the process of cytoprotective autophagy, apoptosis and is therefore directly involved in cell death mechanisms.
92
for example, through downregulation of the adaptor protein SQSTM1/ Casein kinase 2 phosphorylates the cdk11 aminoterminal domain,
p62, resulting in an inefficient form of autophagy from cargo-loading suggesting that cdk11 participates in signaling pathways that include
failure, which, in turn, triggers apoptosis via upregulation of the BH3- casein kinase 2 and that its function may help to coordinate the reg-
76
only protein NBK/Bik. Moreover, cdk inhibitors also induce upregu- ulation of RNA transcription and processing events. So far two iso-
91
77
lation of other BH3-only proteins such as Bim and Noxa. Although it forms of cdk11 have been identified, a larger p110 and a smaller p46
remains to be determined whether these events stem from inhibition of isoform. During Fas- or tumor necrosis factor-α–induced apoptosis,
Kaushansky_chapter 16_p0213-0246.indd 216 9/18/15 11:56 PM