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214 Part IV: Molecular and Cellular Hematology Chapter 16: Cell-Cycle Regulation and Hematologic Disorders 215

M

cdk1
Cyclin B
p21 p15 p16 p18
P
cdc25B P
Cyclin B Cyclin
cdk1 D1, D2, D3 cdk4, 6
P P
G 2 Cyclin B P p107 P P G 1
Cyclin B
cdk1 cdk1 P Rb E2F p107 Rb P Cyclin E PCNA
cdk2
P E2F
Cyclin A P
Cyclin A cdk1 Rb Rb
P E2F Transcription G 0
P factors
(e.g., E2F)
cdc25 Activation of p53 and p21 p21
p73 by DNA damage

p73
p53 Cyclin A Cyclin H
P
cdk2 cdk7
p21 P
cdk2
Cyclin A
MDM2 P Cyclin E
cdk2
p14

cdc25

S

Figure 16–1. Cell-cycle regulation in mammalian cells.

were able to replace deficient cdc28 function in budding yeast: cdk1, factor E2F1 in colorectal cancer. The suppression of β-catenin by E2F1
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cdk2, and cdk3. 15–17 Other cdks are termed cdk4, cdk5, and cdk6. contributes to apoptosis. Therefore, overexpression of cdk8 (and RB)
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Cdk4/6 has been in the focus of tumor-suppressor gene research for accounts for a reduced rate of apoptosis and increased cell growth.
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the past several years, because it complexes with cyclin D (a G cyclin). Cdk9 binds cyclin T and displays a tissue-specific expression pattern.
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1
This complex is an important element in the p16 INK4A -retinoblastoma That cdk9/cyclin T specifically interacts with the tat element of HIV-1
(RB) gene pathway, which is commonly disrupted in cancer. Interest- links this cyclin-dependent kinase directly to the replication pathway of
ingly, the neural cdk5 is also expressed at high levels in certain can- HIV, and circumstantially to HIV-1–related malignancies (e.g., Kaposi
cer types (e.g., myeloma), potentially representing a therapeutic target sarcoma). Cdk10 and cdk11 define a novel class of cyclin-depen-
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in these diseases. Moreover, cdk5 may serve as a prognostic marker dent kinases; both cdks interact with apoptosis-related factors or tran-
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and help to identify patients most likely to respond to treatment (e.g., scription factors such as ets. Cdk10 has two isoforms with different
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with bortezomib). In addition, inhibition of cdk1 and/or cdk5 may functions. A role at the G /M transition has been suggested for the first
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2
contribute to disruption of the unfolded protein response (UPR) sec- isoform of cdk10, whereas the alternative splicing form interacts with
ondary to endoplasmic reticulum (ER) stress inducers. Three tran- the N-terminus of the Ets2 transcription factor. This interaction affects
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scription-regulatory cdks have been characterized. Cdk7 interacts with the G /M transition in mice. Two known cyclin-dependent kinases,
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2
cyclin H and is responsible for phosphorylating cdks on threonine res- cdk12 and cdk13, interact with both forms of cyclin L (cyclin L and L ).
2
1
idues. Cdk8 interacts with cyclin C, Med12, and Med13, and forms a This complex seems to be involved in alterative RNA-splicing, 10,33 and
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complex called “cdk8” subcomplex. Several substrates for cdk8, when thus is involved in the pre–messenger RNA processing machinery. All
complexed with the above-mentioned proteins, have been detected, cyclins share an approximately 150-amino-acid region, called the cyclin
including RNA polymerase II and histone H3. Cdk8 directly antag- box, which interacts with the cdks. The G cyclins (C, D, and E) and the
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1
onizes the repression of β-catenin transcription by the transcription mitotic cyclins (A and B) form distinct categories, although cyclin H,
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Kaushansky_chapter 16_p0213-0246.indd 214 9/18/15 11:56 PM