WEE1

What is WEE1 Protein?

WEE1 protein is a key regulator in the cell cycle, best known for its role in controlling when cells enter mitosis, thereby influencing cell size. It's a kinase enzyme that inhibits Cdk1, preventing cells from dividing too early. Discovered by Paul Nurse, WEE1 is crucial for ensuring cells don't undergo mitosis prematurely. It plays a significant part in cancer research, as disrupting its function with inhibitors can force cancer cells into rapid, destructive division. This potential makes WEE1 an intriguing target in cancer therapy development, albeit with some challenges related to drug toxicity.

What is the Function of WEE1 Protein?

The WEE1 protein is a regulator in the cell cycle, mainly ensuring that cells don't rush into division before they're ready. It works by inhibiting a crucial player in cell division called Cdk1. By doing this, WEE1 pauses the progression into mitosis, giving the cell time to grow and check for any DNA damage that might need repair. It's like a safety checkpoint, making sure cells achieve the right size and conditions before splitting. This is particularly important because if cells divide too quickly or without proper checks, it can lead to problems like cancer.

WEE1 Related Signaling Pathway

WEE1 protein mainly comes into play in the G2/M checkpoint of the cell cycle. It's part of a crucial safety check to make sure everything's in shape before a cell divides. WEE1 stops cell division by keeping the Cdk1 enzyme under control - it does this by adding phosphate groups to it. This ensures cells don't jump into mitosis too soon. When it's time to divide, other proteins step in, reduce WEE1's activity, and let Cdk1 do its job, pushing the cell into mitosis. So, WEE1 acts like a brake, giving cells time to check for errors during DNA replication and growth.

WEE1 Related Diseases

The WEE1 protein is closely linked to the progression of various cancers. It plays a significant role in how cells handle DNA damage, meaning its dysfunction can help cancer cells survive when they should die. This makes WEE1 a potential target for cancer therapy, especially since inhibiting it could push cancer cells to divide recklessly, leading to their demise. However, there's a bit of a catch—it can either act like a friend or foe to tumors, depending on the type and situation, which is why its role in cancer is still being studied.

Bioapplications of WEE1

WEE1 protein's potential in bioapplications mainly revolves around cancer therapy. It's a promising target because of its ability to regulate the cell cycle and hold cells from dividing too soon. By inhibiting WEE1, it forces cancer cells to bypass critical checkpoints, leading to "mitotic catastrophe," which makes the cells more likely to self-destruct. This approach is particularly interesting for treating cancers with faulty DNA repair mechanisms. However, developing WEE1 inhibitors is complex, with challenges involving potential side effects and the need for effective targeting in different cancer types.

Case Study 1: Ponce RKM. et al. JCI Insight. 2022

CIC-DUX4 rearrangements mark a tough-to-treat group of undifferentiated sarcomas, resistant to chemotherapy. This fusion boosts the transcription of genes involved in the cell cycle and DNA replication. It notably raises CCNE1 levels, disrupting the G1/S transition, and makes the cancer rely on the G2/M checkpoint. Our study, using patient-derived samples, finds that CIC-DUX4 sarcomas heavily depend on the G2/M checkpoint regulator WEE1 to survive by controlling DNA damage. Blocking WEE1, either genetically or with drugs, triggers apoptosis in these sarcomas, highlighting WEE1 as a potential treatment target.

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  Fig1. CTG viability assay comparing 2 independent WEE1 siRNAs with scramble control in NCC_CDS1_X1_C1 cells.
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  Fig2. Percent change from baseline in tumor volume for NCC_CDS1_X1_C1.

Case Study 2: Sun L. et al. Drug Dev Res. 2022

Verbascoside, a compound from medicinal plants, shows anti-tumor activity in various cancers, but its effect on liver cancer cell radiosensitivity isn't clear. In studies with Huh7 and HepG2 liver cancer cells, Verbascoside treatment decreased cell viability. It boosted miR-101-3p levels and lowered WEE1 expression, key factors in cell cycle regulation. Combining Verbascoside with X-ray increased liver cancer cell death, affecting proteins like Bax and Bcl-2. Verbascoside enhances radiosensitivity through the miR-101-3p/WEE1 pathway. Blocking miR-101-3p or increasing WEE1 counteracts Verbascoside's effects, highlighting its potential in cancer treatment.

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  Fig3. The interaction between miR-101-3p and WEE1 was validated using the dual-luciferase reporter assay.
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  Fig4. Western blot was used to detect the protein expressions of WEE1 and apoptosis-related proteins Bcl-2 and Bax.

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  Fig1. CIC-DUX4-regulated CCNE1 transcriptional upregulation leads to survival dependence on the G2/M checkpoint kinase WEE1. (Rovingaile Kriska M Ponce, 2022)
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  Fig2. WEE1 suppresses nuclease activities in S phase. (Camilla Reiter Elbæk, 2022)

WEE1 has several biochemical functions, for example, ATP binding,magnesium ion binding,non-membrane spanning protein tyrosine kinase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by WEE1 itself. We selected most functions WEE1 had, and list some proteins which have the same functions with WEE1. You can find most of the proteins on our site.

Function	Related Protein
ATP binding	ALPK2,Adcy4,RAD50,LATS2,STK32A,KCNJ1,PTK6B,ABCE1,MYHZ1.1,PRPF4BB
non-membrane spanning protein tyrosine kinase activity	YES1,BMX,MELK,LYN,STK16,BAZ1B,JAK2A,JAK1,SRMS,JAK3
protein binding	CHMP1B,TBX22,TAF1,STX12,ATP5F1,TMEM30B,FBN2,ZBTB26,EIF5A2,KIF2C
magnesium ion binding	SERPINB1A,INPP1,ADPRHL1,PRTFDC1,NT5C3L,STK3,ENO1,NT5C1B,MARK2,PI4K2A
protein tyrosine kinase activity	TTK,JAK1,FGFR2,AXL,MAP2K7,IGF1RB,CLK3,KIT,CLK4,SRMS

WEE1 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with WEE1 here. Most of them are supplied by our site. Hope this information will be useful for your research of WEE1.

YWHAB;FBXW11;YWHAZ;BTRC;N/A;PLK1;Cdk1;SFN;YWHAG;NEK6;czc8004