Restriction point

Sonic velocity will be established at a restricted point in the pipe, or at the outlet, if the pressure drop is great enough to establish the required velocity. Once the sonic velocity has been reached, the pressure drop in the system will not increase, as the velocity will remain at this value even though the fluid may be discharging into a vessel at a lower pressure than that existing at the point where sonic velocity is established. 

Thus the maximum flow in a pipe occurs when the velocity at the exit becomes sonic. The sonic location may be other than the exit, can be at restrictive points in the system, or at control/safety relief valves. 

D CDK4,CDK6 Progression past restriction point at... 

B. Novak and J. J. Tyson, A model for restriction point control of the mammahan cell cycle. 

Unfortunately, this field is made difficult for a student by the terminology used by biochemists. For example, there is a protein kinase that regulates the cycle between G2 and M, i.e. the second restriction point. This protein is known as maturation (or mitosis) promoting factor, since it promotes entry into mitosis. It phosphorylates a protein, probably a transcription factor, in the nucleus. The kinase has a molecular mass of 34kDa. Hence it is known as p34 cell division kinase, abbreviated to p34-cdc and, since it is regulated at restriction point 2, it is known as p34-cdc-2 protein, which is sometimes written as p34°. This kinase is normally inactive until it binds a cyclin. Hence the active maturation-promoting factor is, in fact, a protein kinase-cyclin complex, which is referred to as p34° °-cyclin complex. It is hoped that this piece of information may help a student (or lecturer from another field) to understand one part of a review article that contains the abbreviation p34° -cyclin complex, without explanation, or other similar pieces of biochemical shorthand. 

Fig. 13.3. Control points of the cell cycle external and internal control mechanisms. Important control points of the cell cycle lie at the end of G2 phase (G2/M transition), in mitosis (metaphase/anaphase transition) and in Gi phase (restriction point). The internal controls are shown as broken arrows and the external controls are shown as solid arrows.

An example of an important cell cycle transition is the restriction point R, which occurs in late G1 phase. Crossing the restriction point is an important decision for further progression in the cell cycle and for entry into S phase. At this point, the cell switches from a growth-factor-dependent state to a growth-factor-independent state. 

Cyclins D and E in mammals are short-hved proteins with a lifetime of only ca. 20 min. Their instability is due to the occurrence of certain sequences in the C-terminal region deletion of these sequences is associated with stabilization of the cyclins (see 13.3.1). These sequence elements are known as PEST sequences, based on their composition. Due to the short half-life, the D type cyclins require a constant stimulus at the transcription level to achieve the concentration in Gi phase necessary for activation of CDK4/6 and to initiate crossing of the restriction point. 

Fig. 13.11. Substrates and phase-spedfic activation of CDKs in the ceU cycle. An overview is shown of the phase-specific activation of the most important CDK-cychn complexes and of selected substrates. The arrows indicate activation and phosphorylation. CDK cycMn-dependent protein kinase p53 tumor suppressor p53 pRb tumor suppressor pRb CDC25 CDC25 phosphatase TFIIIB transcription factor TFIIIB R restriction point.

When mitosis has been completed, the cell requires signals in the form of growth factors to direct towards a new roimd of division. The signals become effective in the first two-thirds of Gi phase. In this time window, the cell is programmed to begin a new cell cycle or to enter Go phase. After a particular point, the restriction point R, no further signals are needed to continue the cell cycle. The cell cycle apparatus is self-contained from this point onwards. S, G2 and M phase occur without external control. The cell cycle may still be halted after crossing the restriction point, however, if the cell detects, via internal control mechanisms or checkpoints, that defects have occurred in the correct course of the phases. 

At the end of mitosis imtil the restriction point R, pRb exists in an underphosphory-lated form. In the underphosphorylated form, pRb has a growth-inhibiting function in that it blocks the activity of activity of transcription factors that control expression of S phase genes. 

During or after crossing the restriction point, pRb exists in a hyperphosphorylated form and it remains in this form until the end of mitosis. In the hyperphosphorylated form, pRb has a growth-promoting fimction. 

The restriction point marks the transition of the cell from a growth-factor-dependent state to a mostly growth-factor-independent state. The fact that changes in the degree... 

Planas-SUva, M. and Weinberg, R.A. The restriction point and control of ceU proUferation (1997) Curr.Op. CeU. Biol. 9, 768-772... 

Several effects of forskolin on B-lymphocytes, the cells of the immune system responsible for the production of immunoglobulins, have further been reported. This diterpene was found to inhibit cellular proliferation of B cells stimulated either by antibodies to surface immunoglobulins (anti-mu), and an antibody to CD20 antigen or 12-O-tetradecanoyl phorbol 13-acetate [219]. There was also a clear inhibition of G1 entry and DNA synthesis, and forskolin maintained its inhibitory effect even when added later after anti-mu stimulation. Additionally, no differences were found in the inhibitory effect of forskolin on neoplastic B cells, as compared to the responses of normal cells. Growth inhibition associated with an accumulation of cells in G1 was later found when cells of the B-lymphoid precursor cell line Reh were incubated with forskolin [220]. In that study, a delay of cells in G2/M prior to G1 arrest was observed, suggesting that important restriction points located in the G1 and G2 phases of the cell cycle may be controlled by forskolin (due to cAMP levels elevation). In a subsequent study [221], it was found that the arrest of Reh cells was accompanied by rapid dephosphorylation of retinoblastoma protein, which was suggested to be a prerequisite for the forskolin mediated arrest of these cells in Gl. 

Fig. 2.8. Consumption (total PCBs s consumption modified 22 congener s consumption of Breivik et al., 2002a see the text) and emission (sum of 22 congeners from Breivik et al., 2002b) of PCBs. Two bars in emission plot are the sum of emissions from 1945 to 2000 from Breivik et al., 2002b (white) and KMOE, 2003b (dark gray). Horizontal lines in the plots mean the first legal restriction point in Korea, 1979 (EBA see Table 2.1). Total consumption of each country (far-right plot) was the sum of annual total PCBs consumption of each country (modified from the default 22 congeners consumption of Breivik et al., 2002a).

Kemp, M.Q., Jeffy, B.D., and Romagnolo, D.F., Conjugated linoleic acid inhibits cell proliferation through a p53-dependent mechanism effects on the expression of G1-restriction points in breast and colon cancer cells, J. Nutr., 133, 3670, 2003. 

As for meteorite analysis, amino acids from such interstellar ice analogues are usually detected after (often acidic) hydrolysis of crude reaction products, and subject to the same interpretation restrictions. Pointing out the formation of peptides [85] (without further arguments) to explain the detection of amino acids in such acid-hydrolyzed irradiated ices is at least questionable since many other precursors can be involved. 

Cells which have spent a long time in Gl lose some of the enzymes typically present in dividing cells — particularly those concerned with DNA synthesis. These cells have traditionally been said to be out of cycle or in GO. The implication of the GO-phase is that to leave GO-cells require a stimulus to urge them past a barrier and back into cycle. Pardee (1974) has suggested that whenever cells are exposed to suboptimal physiological conditions they enter a quiescent phase, and that there is a single restriction point in Gl which regulates their re-entry into a new round of the cell cycle. 

Figure 24.24. Retinoblastoma and cell cycle. Rb regulates the movement of cells through Gi into the S phase of the cell cycle. Regulation of Gi — S phase by Rb represents a key control point in the cell cycle because once the cell has passed the restriction point in Gi (a point in late G, the cell moves into S phase and is now irreversibly committed to replicate its DNA and progress through the entire cell cycle. In early GI phase, Rb binds to E2F and blocks E2F s ability to transcribe S-phase genes. Phosphorylation of Rb by Cdk4/6 and Cdk2 releases E2F from Rb and allows E2F to transcribe S-phase genes. The cell then enters S phase. (Adapted S. Ortega et al. Biochimica et Biophysica Acta. 1602, 73-87, 2002.)...

I 6 Structure-Based Design of Potent and Selective Cdk4 Inhibitors Restriction Point... 

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